ENTITYA TYPEA IDA DATABASEA ENTITYB TYPEB IDB DATABASEB EFFECT MECHANISM RESIDUE SEQUENCE TAX_ID CELL_DATA TISSUE_DATA MODULATOR_COMPLEX TARGET_COMPLEX MODIFICATIONA MODASEQ MODIFICATIONB MODBSEQ PMID DIRECT NOTES ANNOTATOR SENTENCE SIGNOR_ID SCORE RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys68 ETSAAKLkRKYWWKN 9606 BTO:0000007 23353890 t miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. SIGNOR-272094 0.328 IFNAR2 protein P48551 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR form complex binding 9606 11278538 t miannu The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260333 0.906 OPTN protein Q96CV9 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 27181519 f lperfetto Optineurin and TBK1 have also been discovered co-localizing in protein aggregates, and the phosphorylation of optineurin at serine 177 has been shown to be critical to its function in mediating clearance of aggregated proteins via autophagy SIGNOR-262275 0.7 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 15356634 t lperfetto Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128738 0.549 STK4 protein Q13043 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 9606 21808241 t inferred from 70% of family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-269859 0.642 (2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide chemical CHEBI:94760 ChEBI AR protein P10275 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189623 0.8 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 0.2 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD3 protein P08294 UNIPROT up-regulates activity chemical activation 1542024 t lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase SIGNOR-272301 0.8 PRRX1 protein P54821 UNIPROT MAFG protein O15525 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221961 0.338 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 0.409 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr131 KEEPPPLtPPARCAA 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262782 0.2 PTPN6 protein P29350 UNIPROT PKM protein P14618 UNIPROT down-regulates activity dephosphorylation Tyr105 FASDPILyRPVAVAL 9606 26959741 t lperfetto SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs.|SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated hepatocellular carcinoma cells.|SHP-1 dephosphorylates p-PKM2Y105 and further affects the nucleus-related cell proliferation. SIGNOR-276997 0.2 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 0.7 GABRB1 protein P18505 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263760 0.621 AIM2 inflammasome complex SIGNOR-C222 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-263123 0.7 NOXA1 protein Q86UR1 UNIPROT NOX1 protein Q9Y5S8 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264710 0.751 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-158663 0.962 CAY10505 chemical CID:1204893 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190859 0.8 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr165 PSPATDLyQVPPGPG 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-246385 0.803 LCK protein P06239 UNIPROT CD33 protein P20138 UNIPROT up-regulates phosphorylation Tyr340 EMDEELHyASLNFHG 9606 10887109 t lperfetto Human cd33 has two tyrosine residues in its cytoplasmic domain (y340 and y358). When phosphorylated, these tyrosines could function as docking sites for the phosphatases, shp-1 and/or shp-2, enabling cd33 to function as an inhibitory receptor. Lck is effective at phosphorylating y340 SIGNOR-78960 0.271 BRCA1 protein P38398 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 18776923 f miannu We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. SIGNOR-253761 0.2 trichostatin A chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257942 0.8 ABL1 protein P00519 UNIPROT CLASP2 protein O75122 UNIPROT up-regulates quantity phosphorylation 9606 24520051 t miannu We find that Abl binds to and phosphorylates CLASP2 in response to extracellular signals such as serum or PDGF. SIGNOR-279580 0.502 ABL1 protein P00519 UNIPROT MLH1 protein P40692 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 36338985 t miannu We also observed phosphorylation of MLH1 by ABL1 in an in vitro kinase assay with purified recombinant ABL1 and MLH1, confirming there is a direct phosphorylation between ABL1 and the MLH1 component of the MLH1-PMS2 heterodimer.|we propose that ABL1 prevents MLH1 from being targeted for degradation by the chaperone Hsp70 and that in the absence of ABL1 activity at least a portion of MLH1 is degraded. SIGNOR-279581 0.344 AKT1 protein P31749 UNIPROT HIRA protein P54198 UNIPROT up-regulates activity phosphorylation 9606 27515126 t miannu Consistently, HIRA phosphorylation was effectively decreased by Akt1 knockdown and was completely eliminated by the depletion of both Akt1 and Akt2, suggesting that HIRA is phosphorylated primarily by Akt1 and that Akt2 seemed to contribute to HIRA phosphorylation as a supplementary kinase in myoblasts (XREF_FIG).|In this study, HIRA was more efficiently targeted by Akt1 in myoblasts. SIGNOR-279584 0.2 clotrimazole chemical CHEBI:3764 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9606 9770465 t miannu In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR. SIGNOR-259065 0.8 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b3-d) receptor complex SIGNOR-C329 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-263793 0.8 BCOR protein Q6W2J9 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 17296600 t miannu BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin SIGNOR-252241 0.545 HOXD9 protein P28356 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding 9606 10523646 t miannu We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9 SIGNOR-220721 0.508 MAPK3 protein P27361 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-120232 0.316 DLGAP3 protein O95886 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264592 0.8 fingolimod chemical CHEBI:63115 ChEBI S1PR1 protein P21453 UNIPROT down-regulates chemical inhibition 9606 22225501 t gcesareni Sphingosine-1-phosphate (s1p(1)) receptor agonists such as fingolimod (fty-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. SIGNOR-195343 0.8 GAPDH protein P04406 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266495 0.8 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.914 SYP protein P08247 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 33769286 f miannu This study reveals that Syp has a single physiological role in SV recycling, the accurate trafficking, and retrieval of SybII. SIGNOR-264111 0.7 HTR2C protein P28335 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257405 0.277 Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260326 0.7 MAPKAPK2 protein P49137 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 20626350 t gcesareni Mk2 was found to phopsphorylate in vitro the ago2 protein in ser387, which was identified as the major ago2 phosphorylation site in cells.and mutation of ser387 to alanineimpairsago2 localization to therna-containing granules termedprocessing bodies SIGNOR-166615 0.436 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Tyr185 ADSEMTGyVVTRWYR 9606 19230643 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases SIGNOR-184138 0.659 CSNK2A1 protein P68400 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser133 NAIRYIEsLQELLRE -1 9461343 t llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  SIGNOR-250922 0.307 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform SIGNOR-248586 0.469 EXOSC9 protein Q06265 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261388 0.921 lanreotide chemical CHEBI:135901 ChEBI SSTR2 protein P30874 UNIPROT up-regulates activity chemical activation 9606 25060168 t miannu Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. SIGNOR-259242 0.8 PLK1 protein P53350 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser286 KFIMGDSsVQDQWKE 9606 BTO:0000567 phosphorylation:Ser386 LRGAQAAsPAKGEPS 23348582 t lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. SIGNOR-272990 0.354 pregnenolone smallmolecule CHEBI:16581 ChEBI 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268648 0.8 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 t lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238630 0.639 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 0.521 TRIM27 protein P14373 UNIPROT PIK3C2B protein O00750 UNIPROT down-regulates ubiquitination 9606 22128329 t miannu We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity. SIGNOR-177935 0.402 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser950 EGFHPRRsSQGATQM 10090 BTO:0000944 11581251 t lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme SIGNOR-249203 0.602 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252603 0.426 RNF8 protein O76064 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates ubiquitination 9606 20551964 t gcesareni Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist. SIGNOR-265313 0.2 MIB1 protein Q86YT6 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24239288 t miannu BLM is Ubiquitinated by E3 Ligase MIB1.|Moreover, MIB1 mediated BLM degradation in G1 phase appears to be important for DNA double-strand break repair. SIGNOR-278548 0.281 MID2 protein Q9UJV3 UNIPROT SPAG5 protein Q96R06 UNIPROT down-regulates quantity by destabilization ubiquitination Lys409 QTGLVGTkHSTSETE 9606 26748699 t miannu These data indicated that Mid2 was ubiquitinating Astrin at K409 and targeting Astrin for degradation during cytokinesis. SIGNOR-278549 0.309 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 10693759 t gcesareni In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-75362 0.468 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser123 EEEEESEsEDSEDSG 9606 16308564 t lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. SIGNOR-142347 0.2 PRMT1 protein Q99873 UNIPROT TAF15 protein Q92804 UNIPROT up-regulates methylation 9606 19124016 t miannu The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes. SIGNOR-183137 0.431 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249246 0.29 ELOVL proteinfamily SIGNOR-PF93 SIGNOR palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267901 0.8 NR0B2 protein Q15466 UNIPROT PCK2 protein Q16822 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17094771 f 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-254832 0.386 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 0.2 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252604 0.386 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser795 VPPARPGsRGPAPGP 9606 BTO:0000142 15287745 t lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. SIGNOR-127440 0.416 CFII complex complex SIGNOR-C387 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity cleavage 9606 30139799 t lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions SIGNOR-266121 0.8 PAX7 protein P23759 UNIPROT MLL2 complex complex SIGNOR-C88 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-217712 0.304 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser170 ESLDWDSsLVKTFKL 9606 19468302 t llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. SIGNOR-185750 0.638 ITGB1 protein P05556 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257700 0.71 ATM protein Q13315 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity phosphorylation Ser734 S-->L 9606 24162653 t miannu Enhancer of zeste homolog 2 (EZH2), a core catalytic component of polycomb repressive complex 2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability.|We verified that S734 is the predominant ATM site on EZH2 by performing ATM in vitro kinase assays using GST-EZH2 fusion proteins as substrates (Fig. 2b). The phosphorylation signal was nearly lost when the EZH2-S734A mutant was used as substrate SIGNOR-279586 0.458 NFIA protein Q12857 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 t Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. SIGNOR-268871 0.2 JARID2 protein Q92833 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 t lperfetto JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells|Addition of Differentiation Media (DM) to human myoblasts was associated with the induction of MYOG, MYOD and MYL1 and a decrease in JARID2 RNA expression|Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2 (PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS SIGNOR-249599 0.2 KLKB1 protein P03952 UNIPROT F12 protein P00748 UNIPROT up-regulates activity cleavage Arg353 EQPPSLTrNGPLSCG 9606 BTO:0000131 28966616 t lperfetto FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces. SIGNOR-263520 0.606 CELF1 protein Q92879 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity binding 10090 BTO:0000759 16931514 t miannu These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. SIGNOR-262736 0.251 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 0.8 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 t inferred from family member miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-270300 0.8 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Thr739 SEGSGTAtPSALITT 9606 14744793 t lperfetto Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-249481 0.653 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT down-regulates activity phosphorylation Tyr658 GEMDTTSyDVSVLNS 10029 BTO:0000246 16027153 t lperfetto cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity. SIGNOR-246462 0.567 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 8940173 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-247197 0.582 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270887 0.541 SIK2 protein Q9H0K1 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser154 STLYRTQsSSNLAEL -1 27478041 t miannu The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells. SIGNOR-277269 0.322 KDM1A protein O60341 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222121 0.741 AURKA protein O14965 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Ser1070 DSFLQRYsSDPTGAL 9606 23520446 t miannu Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells. SIGNOR-279589 0.393 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 0.2 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 t lperfetto Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo SIGNOR-158418 0.346 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000671 11035029 t fspada The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10 SIGNOR-83191 0.714 canertinib chemical CHEBI:61399 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258095 0.8 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 t miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. SIGNOR-261718 0.647 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr187 FSEEIRFyQLGEEAM 9606 11812778 t gcesareni The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties. SIGNOR-114641 0.31 GBF1 protein Q92538 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 15616190 t miannu GBF1 Stimulates Production of Arf-GTP In Vivo SIGNOR-277400 0.719 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser113 GQKFARKsTRRSIRL 9606 7559487 t miannu Pleckstrin is a substrate for protein kinase c / a combination of phosphopeptide analysis and site-directed mutagenesis shows that three residues in the intervening sequence between the two pleckstrin ph domains become phosphorylated: ser113, thr114, and ser117. /these results suggest that the phosphorylation of at least two of the sites is required for maximal pleckstrin activity SIGNOR-28880 0.28 ADRA1A protein P35348 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257084 0.585 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000776 16914735 t lperfetto Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3_ and enhance the in vivo phosphorylation of gsk3_ on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3_ at serine 9 and decreases the accumulation of cytosolic _-catenin. SIGNOR-148908 0.2 Guanabenz chemical CHEBI:5553 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258910 0.8 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates dephosphorylation 9606 19360021 t gcesareni The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity. SIGNOR-185135 0.488 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 0.838 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 0.8 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser214 TVLTAQEsFSGSLGH -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276216 0.381 TRIM71 protein Q2Q1W2 UNIPROT LIN28B protein Q6ZN17 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001950 24602972 t miannu In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination.  SIGNOR-272054 0.527 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Ser197 SFGLSAMsPTKAAVD 9606 BTO:0001271 18246121 t llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. SIGNOR-160626 0.282 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 0.504 TSSK1B protein Q9BXA7 UNIPROT TSSK1B protein Q9BXA7 UNIPROT up-regulates activity phosphorylation Thr174 GRMALSKtFCGSPAY -1 15733851 t Manara Electrospray Q‐TOF2 mass spectroscopy analysis of a trypsin digested TSSK1 purified from E. coli, revealed that it was phosphorylated at its T‐loop residue (Fig. 2D), indicating that TSSK1 as was previously shown for MELK [18], can autophosphorylate its T‐loop Thr residue. SIGNOR-260823 0.2 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser79 AGALYSGsEGDSESG -1 2046671 t llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. SIGNOR-250956 0.552 ELAVL2 protein Q12926 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266863 0.2 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32433 0.698 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t lperfetto PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. SIGNOR-135980 0.558 PLK1 protein P53350 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by stabilization phosphorylation Ser234 GKFVLKAsLSAPGSE 9606 BTO:0002181 31281496 t miannu We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. SIGNOR-277463 0.249 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT up-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 t miannu We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53. SIGNOR-153719 0.546 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH22 protein Q9UJ99 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265838 0.8 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. SIGNOR-105247 0.372 PHA-767491 chemical CID:11715767 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206115 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4D protein Q08499 UNIPROT up-regulates activity phosphorylation Ser125 CRAMDRTsYAVETGH 9534 12023945 t miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. SIGNOR-275988 0.2 COP1 protein Q8NHY2 UNIPROT ACACA protein Q13085 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271598 0.2 SSTR2 protein P30874 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256827 0.45 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Thr181 PANSFVGtPYWMAPE 9534 BTO:0004055 10559204 t lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. SIGNOR-246298 0.2 CAST protein P20810 UNIPROT CAPN1 protein P07384 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 t lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain SIGNOR-251582 0.915 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236649 0.485 RPS16 protein P62249 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262435 0.877 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 0.865 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) SIGNOR-275490 0.334 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 f gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-141655 0.57 KCNJ10 protein P78508 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 24561201 t miannu KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers SIGNOR-269446 0.8 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 0.8 CHUK protein O15111 UNIPROT TRAF4 protein Q9BUZ4 UNIPROT down-regulates phosphorylation Ser426 KPGTWRGsLDESSLG 9606 22547678 t llicata Traf4 is atypical within its family because it is the only traf family member to negatively regulate innate immune signaling. Ikk_'s phosphorylation of serine-426 on traf4 was required for this negative regulation. SIGNOR-197253 0.384 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10029 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-235748 0.755 ETV2 protein O00321 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24583263 f irozzo We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression. SIGNOR-256006 0.259 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-165216 0.707 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 SIGNOR-242578 0.2 PRKCE protein Q02156 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Ser779 PLDQYSPsFPDTRSS 9606 BTO:0000938 23564461 t lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses. SIGNOR-201671 0.2 SMAD2 protein Q15796 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 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-255023 0.555 NEK9 protein Q8TD19 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 t done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). SIGNOR-273904 0.2 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 0.2 FOXQ1 protein Q9C009 UNIPROT MYLK protein Q15746 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 10896677 t Luana Results from this analysis revealed that the inhibitory activity of HFH-1 was contained within the forkhead DNA-binding domain. Truncated HFH-1 proteins that lack the entire forkhead domain were unable to repress telokin promoter activity, in contrast expression of the forkhead domain alone was able to repress promoter activity SIGNOR-261609 0.2 PRKAA1 protein Q13131 UNIPROT FANCA protein O15360 UNIPROT up-regulates activity phosphorylation Ser347 VQMQREWsFARTHPL 9606 BTO:0001938 27449087 t miannu FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway.  SIGNOR-277264 0.332 CDK1 protein P06493 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 SIGNOR-C17 12372621 t lperfetto Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition. SIGNOR-94160 0.389 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 0.7 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. SIGNOR-251093 0.2 TTK protein P33981 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Thr927 LSRLATNtSAPDLKN 9606 BTO:0000567 31253867 t miannu We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.  SIGNOR-277462 0.2 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser208 DINRGAPsITSVTPR 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262717 0.743 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 0.737 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255876 0.2 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244788 0.2 Microprocessor complex complex SIGNOR-C356 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 24581491 f lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. SIGNOR-264850 0.7 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys137 KNGETSLkPEDFDFT 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275676 0.2 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-181195 0.2 PRKCD protein Q05655 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Thr1224 RYVPPSStDRSPYEK 9606 11877440 t gcesareni We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin SIGNOR-115501 0.336 CLK2 protein P49760 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser142 HSSRRAKsVEDDAEG 9606 BTO:0000567 20682768 t lperfetto Clk2 was reported to regulate its nuclear localization by autophosphorylating serine 141 SIGNOR-167344 0.2 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89213 0.565 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 t miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  SIGNOR-272940 0.87 EGLN2 protein Q96KS0 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 24990963 t lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization SIGNOR-261999 0.856 MAPK12 protein P53778 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser108 LPGASPKsPGLKAMV -1 15850461 t miannu Peptide T2 was sequenced and shown to comprise residues 79–112 of CapZIP, phosphorylated at Ser-108 (Figure 2B). The identity of peptide T1 is unknown. These experiments established that the SAPK3/p38γ substrate was CapZIP. Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown). An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263083 0.504 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276515 0.328 MAPK3 protein P27361 UNIPROT THRB protein P10828 UNIPROT down-regulates activity phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-102224 0.428 RET protein P07949 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 11360177 t gcesareni Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret SIGNOR-108244 0.678 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates cleavage 9606 22972936 t Thrombin acts on protease-activated receptors (PARs), a subfamily of G protein-coupled receptors (GPCR) that participate in a variety of biological process, including chemokine and cytokine release, tissue remodeling, inflammation, proliferation, and angiogenesis. gcesareni The par1 receptor subtype is activated when the n terminus is proteolytically cleaved by the serine protease thrombin, resulting in an irreversible activation of the receptor. Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4). SIGNOR-199007 0.887 HPS3 protein Q969F9 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 t lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6 SIGNOR-260688 0.709 PDIA6 protein Q15084 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0004086 17420453 f Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. SIGNOR-256533 0.7 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-179456 0.895 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265451 0.3 METTL3 protein Q86U44 UNIPROT UCK2 protein Q9BZX2 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 34430596 t lperfetto Furthermore, the m6A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway. SIGNOR-275862 0.2 MAPK3 protein P27361 UNIPROT BRD4 protein O60885 UNIPROT down-regulates activity 9606 32482868 t lperfetto The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. SIGNOR-262048 0.312 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death SIGNOR-67400 0.434 ACSS3 protein Q9H6R3 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271834 0.8 L-serine chemical CHEBI:17115 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 10090 BTO:0000142 12393813 t lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. SIGNOR-268269 0.8 CDC42 protein P60953 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248259 0.942 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248603 0.2 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248923 0.676 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 0.683 PAK1 protein Q13153 UNIPROT TBCB protein Q99426 UNIPROT up-regulates phosphorylation Ser65 GVDDKFYsKLDQEDA 9606 BTO:0000150 15831477 t lperfetto P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function SIGNOR-135464 0.448 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 0.409 AKT1 protein P31749 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser165 LSRLRSPsVLEVREK 9606 BTO:0001950 36797475 t miannu Rabin8 is phosphorylated and activated by Akt in cells grown on stiff ECM. SIGNOR-277816 0.2 FHIT protein P49789 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159867 0.271 AKT1 protein P31749 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 f PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. SIGNOR-254371 0.7 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249399 0.602 TEK protein Q02763 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241541 0.2 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 16440056 f lperfetto The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons. SIGNOR-265058 0.7 SEC13 protein P55735 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265296 0.846 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000876 7964161 t lperfetto Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1. SIGNOR-35077 0.767 GNB1 protein P62873 UNIPROT PLCB1 protein Q9NQ66 UNIPROT down-regulates binding 9606 8870665 t gcesareni These results indicate that g-protein beta gamma subunits constitute a mechanism by which g-protein mediate a rapid and transient plc- beta 1. SIGNOR-44369 0.483 GCK protein P35557 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266458 0.8 BCL2L11 protein O43521 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 t gcesareni Bim, and puma bind with high affinity to all pro-survival proteins SIGNOR-196932 0.837 GATA1 protein P15976 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10523830 f irozzo Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression. SIGNOR-256053 0.518 PPP2R5B protein Q15173 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt. SIGNOR-252615 0.661 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 0.841 CLTCL1 protein P53675 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260662 0.731 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Ser74 TVNQSLLsPLVLEVD 9606 BTO:0000586 19115206 t the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431|The site-specific phosphorylation of keratins induces the disassembly of these filaments, and the balance between their phosphorylation and dephosphorylation controls the continuous exchange of intermediate filament subunits between a soluble pool and polymerized filaments SIGNOR-248340 0.272 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1231 HSLAARYyNWVSFPG 9606 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104076 0.2 XL765 chemical CHEBI:71958 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252660 0.8 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 t gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. SIGNOR-134658 0.596 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 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-164613 0.557 CEBPA protein P49715 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 INO80B protein Q9C086 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270846 0.651 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 0.8 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 0.2 TFEB protein P19484 UNIPROT GNS protein P15586 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276540 0.311 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr34 KDQFPEVyVPTVFEN 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271700 0.2 PRKCA protein P17252 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates phosphorylation Ser312 ASLKRSPsASSLSSM 9606 20519438 t lperfetto Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively SIGNOR-165857 0.2 GART protein P22102 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI down-regulates quantity chemical modification 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-267303 0.8 CAD protein P27708 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267424 0.8 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10617468 t lperfetto 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-73614 0.805 DR1 protein Q01658 UNIPROT NC2 complex complex SIGNOR-C108 SIGNOR form complex binding 9606 BTO:0000567 18838386 t miannu NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex SIGNOR-226405 0.749 AKT proteinfamily SIGNOR-PF24 SIGNOR ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t Threonine phosphorylation of the beta 3 integrin cytoplasmic tail, at a site recognized by PDK1 and Akt/PKB in vitro, regulates Shc binding.|We recently observed that phosphorylation of a threonine (Thr-753), six amino acids proximal to tyrosine 759 in beta(3) of the platelet specific integrin alpha(IIb)beta(3), inhibits outside-in signaling through this receptor.| A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. SIGNOR-251479 0.2 TNRC6B protein Q9UPQ9 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity binding -1 17891150 t miannu The assay showed that full-length TNRC6B binds full-length human AGO2. We have identified and molecularly dissected important sequence and structure features in the conserved Ago hooks of S. pombe Tas3 and human TNRC6B. The effect of Ago hook peptides from the shuttling P-body component TNRC6B in our miRNA-mediated translational repression assay (Fig. 5b), in particular, hints at a novel regulatory role of Ago hooks in miRNA-mediated gene repression mechanisms. SIGNOR-269680 0.796 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t gcesareni In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain (band 4.1 and ezrin/radixin/moesin homology domain). SIGNOR-167654 0.497 LIMS3 protein P0CW19 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-265765 0.562 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 SIGNOR-C3 10942774 t lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. SIGNOR-80797 0.926 Diprenorphine chemical CHEBI:4650 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258789 0.8 CSNK2A2 protein P19784 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro. SIGNOR-251028 0.342 CUL9 protein Q8IWT3 UNIPROT FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 35469017 t miannu M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2. SIGNOR-276717 0.2 C8B protein P07358 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263444 0.593 CEBPE protein Q15744 UNIPROT CEBPG protein P53567 UNIPROT up-regulates activity binding 9606 BTO:0000007 15588942 t miannu C/EBP-epsilon interacts with C/EBP-gamma through the leucine-zipper containing domain. C/EBP-epsilon and C/EBP-gamma synergistically activate transcription of lactoferrin promoter SIGNOR-224900 0.373 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t gcesareni Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. SIGNOR-187854 0.408 DUSP9 protein Q99956 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 21908610 t gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-176589 0.704 NKX3-1 protein Q99801 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates activity binding 9606 16697957 t miannu NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity. SIGNOR-251549 0.369 PRKACA protein P17612 UNIPROT TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by stabilization phosphorylation Ser3 sFPETDFQ -1 31160797 t miannu  These observations suggested that LINK-A expression potentially inhibits PKA phosphorylation/activity and PKA-mediated phosphorylation of TRIM71 at Ser3. SIGNOR-277454 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 KGFNGCDsPEPDGED 10090 BTO:0000944 25733682 t miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  SIGNOR-276887 0.265 ASXL3 protein Q9C0F0 UNIPROT BRD4 protein O60885 UNIPROT up-regulates activity binding 9606 BTO:0000189 32669118 t miannu We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. SIGNOR-266762 0.2 rivaroxaban chemical CHEBI:68579 ChEBI F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206550 0.8 STAT3 protein P40763 UNIPROT IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000876 20032313 f miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB. SIGNOR-254795 0.506 ATM protein Q13315 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser696 NVLSVALsQRTTVPE 9606 21095582 t lperfetto Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability SIGNOR-169999 0.432 CSDE1 protein O75534 UNIPROT FOS protein P01100 UNIPROT down-regulates quantity post transcriptional regulation 10090 BTO:0000944 15314026 t By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv SIGNOR-261145 0.295 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 9398320 t lperfetto Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]. SIGNOR-53735 0.497 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10029 15069075 t lperfetto Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results. SIGNOR-236760 0.723 KPNB1 protein Q14974 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity relocalization 9534 17596301 t lperfetto Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization. SIGNOR-260274 0.27 ARHGAP31 protein Q2M1Z3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260488 0.529 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKP protein Q01813 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-267268 0.8 CHM protein P24386 UNIPROT RABGGTB protein P53611 UNIPROT down-regulates activity binding 9606 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. SIGNOR-265571 0.768 GMPS protein P49915 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI down-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267337 0.8 DVL1P1 protein P54792 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates binding 9606 23151663 t gcesareni Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells. SIGNOR-199451 0.2 MAPK8 protein P45983 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Ser198 GKTKTCEsPVSPIKM -1 28943315 t miannu JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. SIGNOR-277324 0.369 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser184 HPPVLRQsISFSGLP -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-250153 0.699 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation 9606 17604322 t inferred from 70% family members lperfetto In colon cancer cells, the Ras/mitogen‚Äêactivated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‚Äêmutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-269995 0.2 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258459 0.8 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR GATA2 protein P23769 UNIPROT up-regulates activity binding 10090 BTO:0001516 10938104 t We provide evidence that GATA-2 can physically associate with PML-RARα. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL. SIGNOR-259941 0.2 SP1 protein P08047 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15479157 f miannu we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. SIGNOR-255204 0.2 DDIT3 protein P35638 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 f miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260171 0.7 ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. SIGNOR-119546 0.522 RXRA protein P19793 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16671 0.686 DAXX protein Q9UER7 UNIPROT AIRE protein O43918 UNIPROT down-regulates activity binding 9606 BTO:0000567 20185822 t 1 miannu The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE. SIGNOR-239287 0.334 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. SIGNOR-249136 0.33 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 t gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5. SIGNOR-146852 0.821 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-216445 0.263 FUBP1 protein Q96AE4 UNIPROT CCND2 protein P30279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19637194 f irozzo A positive cell cycle regulator that we found down-regulated in Hep3B cells upon FBP1 inactivation was cyclin D2. In addition, Cyclin D2 mRNA levels were diminished in the FBP1 knockdown cells, whereas the amount of Cyclin D1 mRNA remained unaffected. Numerous studies have classified D-type cyclins as cell cycle–promoting oncoproteins important for cellular transformation, and our results suggest that cyclin D2 is a candidate FBP1-regulated oncoprotein in HCC. SIGNOR-259124 0.2 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267324 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 t lperfetto Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 SIGNOR-216880 0.335 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 0.319 AP1 complex SIGNOR-C154 SIGNOR CCND1 protein P24385 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000762 12509763 f lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers.|As a result of stimulating these transcriptional regulators, key cell-cycle regulatory proteins, such as D-type cyclins, are expressed, which enables the cell to progress through the G1 phase of the cell-cycle. SIGNOR-253215 0.62 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1173 QDTSKFWyKADISRE 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187843 0.408 EGFR protein P00533 UNIPROT LRRK1 protein Q38SD2 UNIPROT down-regulates activity phosphorylation Tyr971 TQQTEEQyFQFLAKF 9534 BTO:0000298 22337768 t miannu In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity. SIGNOR-262856 0.343 ZM447439 chemical CHEBI:91376 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207926 0.8 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 0.789 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 10090 BTO:0002572 14966296 t The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. SIGNOR-248390 0.564 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 10090 BTO:0001169 22355693 t We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188 SIGNOR-251644 0.457 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109559 0.679 ginkgolide B chemical CHEBI:5356 ChEBI PTAFR protein P25105 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192684 0.8 NODAL protein Q96S42 UNIPROT ACVR1C protein Q8NER5 UNIPROT up-regulates activity binding 9606 BTO:0004094 15531507 t Indirect_regulation of expression miannu Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation. SIGNOR-251936 0.636 IRF3 protein Q14653 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16699525 t lperfetto Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants SIGNOR-252257 0.665 MAGOH protein P61326 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265243 0.951 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273037 0.541 CNP protein P09543 UNIPROT MBP protein P02686 UNIPROT down-regulates activity 28076777 t SimoneGraziosi We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP). SIGNOR-269269 0.455 MECP2 protein P51608 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates activity binding 9606 BTO:0000007 12473678 t Luana Thus, these results indicate that MeCP2-interacting Dnmt1 has significant maintenance DNA methyltransferase activity and that MeCP2 does not vanish Dnmt1 enzymatic activity. SIGNOR-264541 0.528 ABI1 protein Q8IZP0 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems SIGNOR-253571 0.846 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI SDHB protein P21912 UNIPROT up-regulates activity chemical activation 26083061 t lperfetto Succinate dehydrogenase subunit B contains three Fe-S clusters |The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters SIGNOR-262133 0.8 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275788 0.272 ZFYVE26 protein Q68DK2 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. FYVE-CENT interacts with KIF13A and TTC19 SIGNOR-265538 0.462 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 0.7 EP300 protein Q09472 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12954631 f miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. SIGNOR-253904 0.2 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) smallmolecule CHEBI:58088 ChEBI 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity precursor of 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269809 0.8 GABA-B receptor complex SIGNOR-C336 SIGNOR GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 30541966 t miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. SIGNOR-265064 0.48 NARS1 protein O43776 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270456 0.8 RAB23 protein Q9ULC3 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates 9606 16364285 f gcesareni Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization. SIGNOR-143163 0.2 SPRY4 protein Q9C004 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity 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-253037 0.267 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274095 0.411 DLGAP4 protein Q9Y2H0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264212 0.803 TCF4 protein P15884 UNIPROT SSTR2 protein P30874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 10207097 t Luana Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. SIGNOR-261618 0.358 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275983 0.374 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256322 0.2 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 11041858 t lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex SIGNOR-83226 0.89 FAD(3-) chemical CHEBI:57692 ChEBI ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 t miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. SIGNOR-269469 0.8 DAXX protein Q9UER7 UNIPROT FAS protein P25445 UNIPROT down-regulates binding 9606 9215629 t gcesareni A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation. SIGNOR-49473 0.703 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 t apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes SIGNOR-255377 0.95 MAPK1 protein P28482 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser425 NREKVAAsPKSPTAA 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-140890 0.367 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 0.76 ADORA3 protein P0DMS8 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256671 0.461 RAP1GAP protein P47736 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity binding 9606 BTO:0001949 22173489 t Marta Tosoni Overexpression of Rap1GAP significantly inhibited Rap1 activation, ERK and Akt phosphorylation of HUVECs compared with pcDNA transfection controls SIGNOR-278055 0.329 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 BTO:0002320 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-249002 0.288 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2137 EDRTVPStPTLVVPH 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181022 0.374 ARID1A protein O14497 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270689 0.807 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 15647376 t llicata N this study we have demonstrated that ezrin y145 is a direct target for phosphorylation by the tyrosine kinase src evidence from this study suggests that a positive feedback loop exists whereby src-mediated ezrin y145 phosphorylation sustains src activity._ SIGNOR-133227 0.648 CTNND2 protein Q9UQB3 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252134 0.447 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 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-249333 0.581 BRMS1 protein Q9HCU9 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0000093 30416854 t miannu Our results have showed that BRMS1 together with LSD1 are required for inhibition of breast cancer cell migration and invasion. Collectively, these findings demonstrate that BRMS1 executes transcriptional suppression of breast cancer metastasis by associating with the LSD1 and thus can be targeted for breast cancer therapy. SIGNOR-266409 0.257 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 0.339 CDK2 protein P24941 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR form complex binding 9606 19056339 t lperfetto We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2. SIGNOR-182569 0.977 ESR2 protein Q92731 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253943 0.29 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260258 0.7 SRC protein P12931 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Tyr156 YGPRAEEyEFLTPVE 9606 16943322 t llicata We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42. SIGNOR-149282 0.399 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 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-217436 0.93 PRKCA protein P17252 UNIPROT PPP1R16B protein Q96T49 UNIPROT down-regulates activity phosphorylation Ser331 SQLRHKSsLSRRTSS -1 27939168 t done miannu PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function. SIGNOR-273802 0.2 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR BCOR protein Q6W2J9 UNIPROT up-regulates activity binding 10090 BTO:0000944 12776190 t irozzo As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis. SIGNOR-256142 0.2 EPAS1 protein Q99814 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271579 0.278 NF90-NF45 complex SIGNOR-C443 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by repression 10116 25566957 f miannu In the present study, we investigated the expression profiles of NF45 in the sciatic nerve of adult rats following crush injury.  in the TNF-α-induced Schwann cell proliferation assay, protein level of NF45 and cyclin E was elevated while expression of p21 was down-regulated. Further, when NF45 was knocked down, Schwann cell proliferation was interrupted and the expression of cyclin E was attenuated, while the expression of p21 was up-regulated. To repress the expression of p21 is one of the basic mechanisms for NF45-regulated cell proliferation. SIGNOR-268491 0.248 LPAR5 protein Q9H1C0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256997 0.2 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. SIGNOR-153944 0.691 HBA1 protein P69905 UNIPROT EDN1 protein P05305 UNIPROT down-regulates activity 9606 8573884 f Regulation of localization miannu Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury. SIGNOR-251767 0.261 GAS6 protein Q14393 UNIPROT MERTK protein Q12866 UNIPROT up-regulates binding 9606 BTO:0000975 8939948 t gcesareni We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily. SIGNOR-44953 0.762 TGM2 protein P21980 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16407273 t gcesareni Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. SIGNOR-265369 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr326 TSSSQLStPKSKQSP 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250659 0.405 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 0.2 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity dephosphorylation Tyr576 RYMEDSTyYKASKGK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254719 0.243 PDK3 protein Q15120 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-109609 0.871 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257966 0.8 BLOC-2 complex SIGNOR-C252 SIGNOR KIF13A protein Q9H1H9 UNIPROT up-regulates activity binding 9606 30404817 t lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. SIGNOR-260702 0.257 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260963 0.7 KCNS3 protein Q9BQ31 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 10029 BTO:0000246 10484328 t miannu We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily. SIGNOR-269448 0.8 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 8266078 t gcesareni Il-2r gamma was demonstrated to be a component of the il-4 receptor on the basis of chemical cross-linking data, the ability of il-2r gamma to augment il-4 binding affinity, and the requirement for il-2r gamma in il-4-mediated phosphorylation of insulin receptor substrate-1. SIGNOR-37362 0.83 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205819 0.8 CDK1 protein P06493 UNIPROT FANCG protein O15287 UNIPROT up-regulates phosphorylation Ser387 PRFSPPPsPPGPCMP 9606 15367677 t gcesareni S387a mutant abolished fancg fusion protein phosphorylation by cdc2. SIGNOR-129061 0.355 MARCHF9 protein Q86YJ5 UNIPROT LILRB1 protein Q8NHL6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271534 0.2 PDPK1 protein O15530 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Thr507 FGESRAStFCGTPDY 9606 BTO:0000007 9748166 t miannu PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505) SIGNOR-250269 0.577 leuprolide acetate chemical CHEBI:63597 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 22416801 t miannu Clinical data have shown that the GnRH antagonist, degarelix, is associated with more rapid PSA suppression and improved PSA PFS compared with the GnRH agonist, leuprolide. SIGNOR-259163 0.8 C5AR1 protein P21730 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263462 0.7 MAP2K6 protein P52564 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates phosphorylation 9606 9430721 t gcesareni The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms. SIGNOR-54947 0.702 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 15664191 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk SIGNOR-133345 0.637 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277226 0.464 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118027 0.717 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258626 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 BTO:0000222 14749395 t lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. SIGNOR-216920 0.319 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser283 RSVPEPLsPVSSLQA -1 16027724 t GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) SIGNOR-251227 0.381 CDK1 protein P06493 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr412 DTEIANStPNPKPAA 9606 16378098 t gcesareni Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase. SIGNOR-143387 0.759 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT up-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin) SIGNOR-251134 0.526 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser392 ERLRLSPsPTSQRSR 9606 18815303 t gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm SIGNOR-181318 0.536 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 t gcesareni Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity. SIGNOR-102652 0.497 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 t lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. SIGNOR-110399 0.395 EP300 protein Q09472 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254260 0.2 SMARCB1 protein Q12824 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates 9606 12226744 f miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. SIGNOR-92785 0.313 CDK9 protein P50750 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity phosphorylation Thr439 FTPSGILtPHALGSR -1 26728557 t miannu Among the RNA processing factors phosphorylated by Cdk9 was the 5'-to-3' "torpedo" exoribonuclease Xrn2, required in transcription termination by Pol II, which we validated as a bona fide P-TEFb substrate in vivo and in vitro. Phosphorylation by Cdk9 or phosphomimetic substitution of its target residue, Thr439, enhanced enzymatic activity of Xrn2 on synthetic substrates in vitro.  SIGNOR-277194 0.278 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 0.298 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 t lperfetto C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1 SIGNOR-86013 0.385 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity precursor of -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267245 0.8 TRIM62 protein Q9BVG3 UNIPROT CARD9 protein Q9H257 UNIPROT up-regulates activity ubiquitination Lys125 LLMTEVMkLQKKVQD 9606 26488816 t miannu Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG). SIGNOR-278552 0.51 PRLHR protein P49683 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257280 0.264 CHD8 protein Q9HCK8 UNIPROT SOX7 protein Q9BT81 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268922 0.2 ID3 protein Q02535 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241134 0.53 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr94 SSLPEGYyEEAVPLS 9534 9655255 t lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. SIGNOR-246363 0.572 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR BIN1 protein O00499 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136399 0.277 RCSD1 protein Q6JBY9 UNIPROT CAPZA1 protein P52907 UNIPROT up-regulates binding -1 15850461 t miannu An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B). Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263088 0.667 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258775 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr37 EECDQNWyKAELNGK 9606 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246289 0.2 MAPK1 protein P28482 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 t lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. SIGNOR-249413 0.368 APH1B protein Q8WW43 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12522139 t gcesareni Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity. SIGNOR-97107 0.911 NTN1 protein O95631 UNIPROT UNC5C protein O95185 UNIPROT up-regulates binding 9606 10399920 t gcesareni We provide evidence that netrin-1 triggers the formation of a receptor complex of dcc and unc5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting dcc-mediated attraction to unc5/dcc-mediated repulsion. SIGNOR-69047 0.832 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Thr120 QGSPRTStPFGSGRV 9606 17310276 t lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 SIGNOR-153308 0.341 PRKDC protein P78527 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform SIGNOR-252447 0.754 EGFR protein P00533 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates activity phosphorylation Tyr433 AALDTIQySKHPPPL 9606 31931029 t miannu Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking. SIGNOR-277500 0.33 NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 t lperfetto We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located. SIGNOR-236321 0.615 TYMS protein P04818 UNIPROT dUMP(2-) smallmolecule CHEBI:246422 ChEBI down-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268234 0.8 EGFR protein P00533 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates phosphorylation Tyr570 SSNFDSIyICPSTFA 9606 20029029 t gcesareni A negative feedback loop consisting of egfr-mediated phosphorylation of hdac6 tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. SIGNOR-162431 0.44 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 0.821 IGF1R protein P08069 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15829723 f apalma Mechanical loading increases IGF-I release, and IGF-I can stimulate Ca2+ influx and thereby activate calcineurin SIGNOR-255100 0.8 PRKCZ protein Q05513 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Thr110 SHSRQAStDAGTAGA 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. SIGNOR-276877 0.277 ELOVL5 protein Q9NYP7 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267898 0.8 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 t lperfetto Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not SIGNOR-236424 0.87 BMPR1A protein P36894 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 t lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-255257 0.564 PELI1 protein Q96FA3 UNIPROT HPD protein P32754 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0003036 31537781 t lperfetto Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. SIGNOR-272959 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange. SIGNOR-252792 0.2 MST1R protein Q04912 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 35569509 t lperfetto This suggests that by interacting with Sdc4, either directly or indirectly, RON is activated via transphosphorylation when clustered, engages the ABL1 SH2 domain, and activates ABL1 by phosphorylation. SIGNOR-272999 0.272 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255115 0.745 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser717 VYKSPVVsGDTSPRH 9606 BTO:0000590 12387894 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249355 0.739 PCSK2 protein P16519 UNIPROT OXT protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270328 0.265 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 0.923 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-86684 0.34 E2F1 protein Q01094 UNIPROT LRBA protein P50851 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15064745 f miannu We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. SIGNOR-253846 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262995 0.2 RUNX1 protein Q01196 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30500954 f irozzo Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. SIGNOR-259133 0.334 TGFA protein P01135 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000584 16585207 t Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines gcesareni Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo. SIGNOR-93199 0.899 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser518 LSASPRMsGFIYQGK 9606 25009260 t lperfetto Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome SIGNOR-205234 0.2 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 0.8 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser532 KSPAEAKsPEKEEAK 10116 9592082 t lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. SIGNOR-249425 0.368 PRKAA1 protein Q13131 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo SIGNOR-256134 0.2 MTA1 protein Q13330 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263842 0.807 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Tyr183 NSFVGTPyWMAPEVI 9534 BTO:0004055 10559204 t lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. SIGNOR-246302 0.2 dopamine smallmolecule CHEBI:18243 ChEBI 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI up-regulates quantity precursor of 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-264177 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.791 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser101 AAPEAGAsPVEKEAP -1 8034575 t lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. SIGNOR-248909 0.73 SSTR5 protein P35346 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256690 0.496 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-216868 0.339 AKT2 protein P31751 UNIPROT ANKRD2 protein Q9GZV1 UNIPROT up-regulates phosphorylation Ser99 QERVRKTsLDLRREI 10090 BTO:0000165;BTO:0000222 21737686 t llicata In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions. SIGNOR-236978 0.414 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates ubiquitination 9606 16123311 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-139954 0.608 ECM stimulus SIGNOR-ST20 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259047 0.7 CSF1R protein P07333 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24890514 f apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation SIGNOR-255572 0.286 CDK1 protein P06493 UNIPROT PIK3C2A protein O00443 UNIPROT down-regulates activity phosphorylation Ser259 KVSNLQVsPKSEDIS 9606 12719431 t lperfetto Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk SIGNOR-100903 0.281 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser689 KGVDFESsEDDDDDP -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265895 0.2 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000590 9832145 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249354 0.739 PI3K complex SIGNOR-C156 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. SIGNOR-255577 0.7 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni Crk can interact directly with tyrosine kinase receptors and can transmit signals downstream SIGNOR-185667 0.609 MUC1 protein P15941 UNIPROT KLF4 protein O43474 UNIPROT up-regulates activity binding 17308127 t lperfetto Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. Our results show that MUC1-C binds constitutively to KLF4, occupies PE21 with KLF4, and enhances the KLF4 occupancy of PE21.  SIGNOR-270543 0.281 CHKA protein P35790 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017875 t miannu These data suggests that CKI overexpression may overcome a requirement for phosphorylation at the major mTOR sites in DEPTOR for formation of the degron and are consistent with our finding that CKI can phosphorylate S286 and S287 in DEPTOR in vitro in the absence of mTOR. SIGNOR-279605 0.2 MC3R protein P41968 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity 9606 22215617 t lperfetto We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus. SIGNOR-253068 0.547 imatinib chemical CHEBI:45783 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258227 0.8 UCHL3 protein P15374 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-270832 0.872 MAS1 protein P04201 UNIPROT AGTR1 protein P30556 UNIPROT down-regulates activity binding 9606 BTO:0000007 15809376 t miannu our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex SIGNOR-260626 0.276 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188135 0.2 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269103 0.8 CDK5RAP2 protein Q96SN8 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity binding 9606 BTO:0000567 19282672 t Giulio We show here that inhibition of CDK5RAP2 expression causes chromosome mis-segregation, fails to maintain the spindle checkpoint, and is associated with reduced expression of the spindle checkpoint proteins BUBR1 and MAD2 and an increase in chromatin-associated CDC20.|We found that the APC activator CDC20, but not others we exam-ined, was present in the CDK5RAP2 immunocomplex in HeLa cell extracts (Fig. 3A). CDK5RAP2 was detected in the CDC20 immunocomplex as well (Fig. 3B). SIGNOR-260311 0.313 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. SIGNOR-173331 0.747 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser14 LNVIKMKsSDFLESA -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276161 0.2 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Thr211 TVGGKLDtFCGSPPY 9606 BTO:0000568 12879020 t lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. SIGNOR-104063 0.315 CDK1 protein P06493 UNIPROT STMN1 protein P16949 UNIPROT up-regulates activity phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 8125092 t lperfetto SIGNOR-279802 0.641 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-250822 0.494 ADAM17 protein P78536 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 10882063 t gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. SIGNOR-78903 0.739 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65273 0.442 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr381 VIHSPGFyTGKPGYK 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277866 0.565 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser758 PVVFTVGsPPSGSTP 9606 BTO:0001938 21383122 t lperfetto When cells are replenished with rich medium, mtor is activated;it phosphorylates serine 638 and serine 758. The phosphorylation of ulk1 at serine 758 then leads to reassociation between ulk1 and ampk. SIGNOR-172541 0.849 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 0.426 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268279 0.8 MMP17 protein Q9ULZ9 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272362 0.7 PAK1 protein Q13153 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity phosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277181 0.367 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t lperfetto We have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl SIGNOR-99215 0.2 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72695 0.773 PPP2R2A protein P63151 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity binding 10090 18042541 t gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). SIGNOR-252637 0.484 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. SIGNOR-248646 0.317 MYC protein P01106 UNIPROT ST3GAL3 protein Q11203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-253962 0.2 KDM5A protein P29375 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265334 0.2 CAV3 protein P56539 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255997 0.507 PRKCB protein P05771 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E . SIGNOR-248946 0.348 STRADA protein Q7RTN6 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity binding 9606 12805220 t Gianni Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 SIGNOR-247560 0.939 MAPK3 protein P27361 UNIPROT TRPV3 protein Q8NET8 UNIPROT up-regulates activity phosphorylation Thr264 EGFYFGEtPLALAAC 9606 BTO:0000552 29084846 t done miannu We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis. SIGNOR-273672 0.2 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates phosphorylation 9606 16469705 t gcesareni Here we show that tnfalpha-mediated jnk activation accelerates turnover of the nf-kappab-induced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activation of the e3 ubiquitin ligase itch, which specifically ubiquitinates c-flip and induces its proteasomal degradation. SIGNOR-144456 0.654 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252863 0.765 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10644769 f miannu these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation. SIGNOR-253873 0.383 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249120 0.329 IFITM3 protein Q01628 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates activity binding 10090 32879487 t miannu IFITM3 directly binds to γ-secretase. IFITM3 KO reduced γ-secretase activity for both Aβ40 and Aβ42 cleavages as compared to the EV (empty vector guide RNA) cell line by 36% and 27%, respectively (Fig. 2d, bar 1 and 3). SIGNOR-266303 0.2 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 0.2 frovatriptan chemical CHEBI:134991 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation -1 9986723 t miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). SIGNOR-259073 0.8 F2RL1 protein P55085 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256895 0.2 FGF14 protein Q92915 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253445 0.244 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 CDK2 protein P24941 UNIPROT CCNO protein P22674 UNIPROT up-regulates activity phosphorylation Ser81 PSAARGGsPLPGPAQ 9606 BTO:0000007 25364462 t lperfetto Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O|CKD2 phosphorylates the 81st serine residue of cyclin O SIGNOR-275615 0.453 SMARCC1 protein Q92922 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270606 0.798 BST1 protein Q10588 UNIPROT nicotinic acid-adenine dinucleotide phosphate smallmolecule CHEBI:76072 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264249 0.8 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr988 RVDSDNAyIGVTYKN 9823 BTO:0004007 7535778 t miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. SIGNOR-250252 0.2 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206331 0.8 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 t gcesareni It has been shown that the c-terminal domains of ck2? Are phosphorylated by cdc2 and interact with the peptidyl-prolyl isomerase pin1 in a cell cycle-dependent manner SIGNOR-161843 0.355 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 0.8 MMP3 protein P08254 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE 9606 BTO:0000206 9202061 t lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374 SIGNOR-266986 0.738 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Thr658 VGGVVIAtVIVITLV -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261792 0.489 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-171770 0.914 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates activity phosphorylation Thr227 LEPEALHtPTLMTTP 9606 27816489 t Manara PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. SIGNOR-260879 0.2 PHF12 protein Q96QT6 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266994 0.2 FYN protein P06241 UNIPROT CD79A protein P11912 UNIPROT up-regulates activity phosphorylation Tyr199 NLDDCSMyEDISRGL -1 9531288 t Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). SIGNOR-251153 0.596 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr585 PPGLEYCyNPSHNPE 10116 19224897 t lperfetto Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region SIGNOR-235682 0.2 PTGDR protein Q13258 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256755 0.593 RPS6KB1 protein P23443 UNIPROT MXI1 protein P50539 UNIPROT down-regulates activity phosphorylation Ser160 MERIRMDsIGSTISS 9606 29507620 t miannu Phosphorylation of Mxi1 by S6K1 at S160 site promotes its binding to beta-Trcp and ubiquitin mediated degradation.|The above findings demonstrate that S6K1 and beta-Trcp negatively regulates the stability of Mxi1 through ubiquitin proteasome pathway. SIGNOR-278231 0.351 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 t gcesareni Mcl-1 can be rapidly degraded by certain death-inducing signals, but it is able to be readily induced by diverse survival cytokines such as epidermal growth factor, vascular endothelial growth factor, granulocyt-macrophage colony-stimulating factor, and interleukin 3 through phosphatidy-linositol-3-oh kinase/akt, mek/mapk, or janus-activated kinase/stat signaling cascades SIGNOR-179816 0.526 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258730 0.8 SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 9539737 f gcesareni Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands SIGNOR-170607 0.448 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257877 0.8 HRH1 protein P35367 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257376 0.428 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. SIGNOR-167646 0.595 NR3C1 protein P04150 UNIPROT RXRA protein P19793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12573484 f gcesareni Physiological concentrations of glucocorticoids increase cellular cyp2c9 (and cyp3a5) but also car, rxr and pxr levels via a gr-mediated mechanism SIGNOR-98102 0.464 FBXO11 protein Q86XK2 UNIPROT DTL protein Q9NZJ0 UNIPROT down-regulates binding 9606 23478441 t miannu We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation. SIGNOR-192325 0.544 p38 proteinfamily SIGNOR-PF16 SIGNOR CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276362 0.2 ACVR1 protein Q04771 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 18801898 f gcesareni Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. SIGNOR-243185 0.248 NPTX1 protein Q15818 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control SIGNOR-260413 0.2 IL1B protein P01584 UNIPROT ITGA2 protein P17301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001596 1744142 f lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. SIGNOR-253356 0.274 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-236236 0.965 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271331 0.2 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 BTO:0000459 18621737 t lperfetto Through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2. SIGNOR-179449 0.873 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 0.381 FYN protein P06241 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276371 0.357 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 f Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass SIGNOR-195684 0.584 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 0.2 TMPRSS2 protein O15393 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25122198 t miannu we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program. SIGNOR-263657 0.2 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI TYRO3 protein Q06418 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190410 0.8 ITCH protein Q96J02 UNIPROT BID protein P55957 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20392206 t miannu The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid SIGNOR-271415 0.352 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193627 0.8 COL1A2 protein P08123 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000165 12496264 t lperfetto Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. SIGNOR-253346 0.477 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes. SIGNOR-266028 0.7 AKT2 protein P31751 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-235852 0.678 ARHGEF6 protein Q15052 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 BTO:0000599 23776207 f lperfetto Activation of ARF6 promotes cortical actin assembly (9) and plasma membrane remodeling  SIGNOR-272236 0.7 GSK3A protein P49840 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B SIGNOR-251215 0.368 PDGFRB protein P09619 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 11896619 t miannu The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway SIGNOR-115843 0.58 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24392140 t lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253385 0.455 TTL protein Q8NG68 UNIPROT TUBA3E protein Q6PEY2 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176924 0.46 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser1255 CLTERAMsWQDRARQ -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274059 0.303 EEF1A1P5 protein Q5VTE0 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269559 0.8 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-256441 0.364 DLX2 protein Q07687 UNIPROT MSX2 protein P35548 UNIPROT down-regulates activity binding 10090 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240911 0.392 FANCF protein Q9NPI8 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263242 0.908 TUBG1 protein P23258 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 f miannu It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly SIGNOR-261423 0.7 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT down-regulates activity cleavage Pro21 FLLSYAVpSCGRSVE -1 8753751 t lperfetto Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments. SIGNOR-270546 0.422 DSN1 protein Q9H410 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 t lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits SIGNOR-265189 0.902 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 0.8 LEF1 protein Q9UJU2 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f irozzo Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-256281 0.6 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270907 0.558 fentanyl chemical CHEBI:119915 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258939 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells SIGNOR-252784 0.2 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR LEFTY2 protein O00292 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269251 0.419 CDK2 protein P24941 UNIPROT LIG3 protein P49916 UNIPROT down-regulates phosphorylation Ser210 TTTGQVTsPVKGASF 9606 17040896 t llicata Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm. SIGNOR-150121 0.418 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1035 NMDAPPLsPYPFVRT 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) SIGNOR-104711 0.68 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 t gcesareni These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites. SIGNOR-83407 0.2 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Ser452 PVKTLPFsPSQFLNF BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250735 0.718 METTL3 protein Q86U44 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000567 27117702 t miannu Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.  SIGNOR-265954 0.331 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 0.2 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 0.338 CHUK protein O15111 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation 9606 27027448 t miannu In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines. SIGNOR-279607 0.511 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser867 SPVSVGSsPPVKNIS 9606 BTO:0000093 15383283 t miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. SIGNOR-250106 0.526 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 16669787 t miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 SIGNOR-146521 0.524 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. SIGNOR-138912 0.341 SRC protein P12931 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation 9606 15791211 t miannu An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP. SIGNOR-279487 0.759 sertindole chemical CHEBI:9122 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258542 0.8 CDK1 protein P06493 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 SIGNOR-C17 19107194 t gcesareni We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells SIGNOR-182863 0.528 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. SIGNOR-146897 0.819 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr41 GIHSGATtTAPSLSG 9606 19667122 t lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. SIGNOR-187582 0.2 CSNK2A1 protein P68400 UNIPROT SLC29A1 protein Q99808 UNIPROT up-regulates activity phosphorylation Ser254 ETKLDLIsKGEEPRA -1 17520485 t miannu These data suggest that inhibition of CK2-mediated phosphorylation at Ser254 had the same effect on transporter function as the actual loss of Ser254 in mENT1a, implying that this site is constitutively phosphorylated by CK2.  SIGNOR-276063 0.2 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 0.331 CLK1 protein P49759 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation 9606 23707382 t miannu In a previous study, we showed that CLK1 phosphorylates SRSF1 to a greater extent than SRPK1, inducing a hyper-phosphorylated state that can be readily detected by a gel shift on SDS-PAGE. xref In xref , the phosphorylation of SRSF1 in single turnover experiments using SRPK1 and CLK1 is shown.|Unlike SRPK1, CLK1 induces a unique structural form of SRSF1 observed by SDS-PAGE that is exclusively the result of Ser-Pro rather than Arg-Ser phosphorylation. SIGNOR-279608 0.673 DYRK1A protein Q13627 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity phosphorylation Ser62 S-->E 9606 24901999 t miannu We also found that DYRK1A phosphorylated c-Myc on Ser62, priming phosphorylation on Thr58 by GSK3\u03b2 and subsequent degradation.|c-Myc expression is down-regulated by DYRK1A. SIGNOR-279609 0.374 PHF12 protein Q96QT6 UNIPROT TLE4 protein Q04727 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-266989 0.2 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257927 0.8 PRKCA protein P17252 UNIPROT RAB37 protein Q96AX2 UNIPROT down-regulates activity phosphorylation Thr172 YGVPFLEtSAKTGMN 9606 BTO:0002877 29312551 t done miannu We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility.  SIGNOR-273803 0.2 PTPN2 protein P17706 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity dephosphorylation 9606 33122197 t miannu Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. SIGNOR-277039 0.276 Upadacitinib chemical CID:58557659 PUBCHEM JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 33240390 t Upadacitinib (ABT-494) is another selective inhibitor of JAK1 undergoing clinical trials to determine its benefit for several inflammatory diseases SIGNOR-272504 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269335 0.726 TFAP2A protein P05549 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 t miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 SIGNOR-253636 0.259 LFNG protein Q8NES3 UNIPROT DLL1 protein O00548 UNIPROT up-regulates binding 9606 11346656 t gcesareni The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng SIGNOR-107699 0.447 desipramine chemical CHEBI:47781 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9400006 t miannu In the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.in the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.Thus, amitriptyline, imipramine, nortriptyline and desipramine showed high affinity for the SERT, particularly the human version, and for the NET in which the secondary amines were more potent. SIGNOR-258679 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-251470 0.2 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 12857726 t gcesareni Our results demonstrate that ptp1b plays an important role in the integrin-mediated dephosphorylation of lat in human platelets and is involved in the control of irreversible aggregation upon fcgammariia stimulation. SIGNOR-103599 0.504 RAPGEF3 protein O95398 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 t miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. SIGNOR-263956 0.71 KLF10 protein Q13118 UNIPROT TGFBI protein Q15582 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 18359287 t lperfetto Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia. SIGNOR-253212 0.242 PRKG1 protein Q13976 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates activity phosphorylation Ser101 RRRRGAIsAEVYTEE 9606 BTO:0002181 29378851 t miannu  In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells. SIGNOR-277383 0.234 DLC1 protein Q96QB1 UNIPROT MYH9 protein P35579 UNIPROT down-regulates activity binding 9606 BTO:0004006 phosphorylation:Ser1943 RKGAGDGsDEEVDGK 26977077 t miannu Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. Dlc1 interacts with phosphorylated Myh9 (Ser-1943). This association of Dlc1 with S1943 phosphorylated Myh9, suggests that Dlc1 may be involved in reduced Myh9 filament stability. SIGNOR-269283 0.2 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242599 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276099 0.264 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 20145185 t gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-163730 0.8 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 11948419 t gcesareni Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo. SIGNOR-116499 0.374 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 10191262 t miannu The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp SIGNOR-250274 0.65 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR KDM5B protein Q9UGL1 UNIPROT down-regulates activity 9606 35217626 t SaraGualdi Our transcriptomic profiling in AML further identified Kdm5b (also known as Jarid1b, Plu-1, or RBP2-H1), a multifunctional demethylase that can remove histone H3 lysine 4 tri/di-methylation (H3K4me3/2), to be a critical downstream target repressed by PRC2. SIGNOR-271577 0.362 OGA protein O60502 UNIPROT PFKL protein P17858 UNIPROT up-regulates activity deglycosylation Ser529 CVIPATIsNNVPGTD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267608 0.2 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI GRM2 protein Q14416 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-193728 0.8 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-252901 0.494 CIITA protein P33076 UNIPROT HLA-DRB3 protein P79483 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10886240 f These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. SIGNOR-254011 0.2 MXI1 protein P50539 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002036 11875718 t Luana Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression | Mxi1 inhibits the promoter activity of the cyclin B1 gene. SIGNOR-266064 0.266 PDK1 protein Q15118 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3. SIGNOR-250264 0.306 TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252067 0.85 FLNA protein P21333 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 11706047 t lperfetto We conclude that FLNa is essential in cells that express it for stabilizing orthogonal actin networks suitable for locomotion.  SIGNOR-261851 0.7 GRIA4 protein P48058 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-264950 0.8 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser789 VSAGPRPsPLPSPQP 9606 20005250 t miannu Further, investigation revealed that MLK3 was phosphorylated at two residues Ser789 and Ser793 by GSK3beta.|When, these two sites on MLK3 were mutated to non-phosphorable Ala, the activation of MLK3 by GSK3\u03b2 was blocked, and neuronal cell death upon NGF withdrawal also prevented ( xref ). SIGNOR-279616 0.336 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 0.888 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT down-regulates activity binding 9606 19956691 t Regulation miannu We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. SIGNOR-251865 0.688 JAKMIP1 protein Q96N16 UNIPROT TUBB protein P07437 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000661 15277531 t SARA In Jamip1, the N-terminal region mediates the association with microtubules, when highly expressed, N-ter drastically affects the organization of microtubules that appear to be bundled, stabilized against the depolymerizing effect of nocodazole, and enriched in acetylated tubulin. SIGNOR-260987 0.2 GDAP1 protein Q8TB36 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto However, it remains elusive if additional proteins are involved in the regulation of mitochondrial fission, such as proposed fission factor GDAP1 SIGNOR-272977 0.7 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 0.7 NEK2 protein P51955 UNIPROT SRSF1 protein Q07955 UNIPROT down-regulates activity phosphorylation 9606 24369428 t miannu First, NEK2 interacts with and phosphorylates SRSF1. SIGNOR-279344 0.385 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 0.429 CREB5 protein Q02930 UNIPROT MAPKAPK3 protein Q16644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002814 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253807 0.25 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235467 0.563 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131403 0.2 lofexidine chemical CHEBI:51368 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 t Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  SIGNOR-258331 0.8 AURKC protein Q9UQB9 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates activity phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 29050234 t miannu AURKC directly induces IkappaBalpha activation via an interaction between the two proteins, leading to phosphorylation of IkappaBalpha.|AURKC phosphorylates IkappaBalpha on S32 and binds its ankyrin repeat domain. SIGNOR-278470 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264954 0.7 JUN protein P05412 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements SIGNOR-198834 0.7 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000567 8621729 t lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222. SIGNOR-236451 0.74 MDH2 protein P40926 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266288 0.8 TFAP4 protein Q01664 UNIPROT SP1 protein P08047 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-226593 0.356 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates activity phosphorylation Thr208 TFGNKLDtFCGSPPY -1 18424437 t miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. SIGNOR-276165 0.588 YWHAG protein P61981 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261723 0.266 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 0.593 CDK4 protein P11802 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity phosphorylation Ser430 KYTYGQSsMSPLPQM 9606 23469153 t miannu In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro . SIGNOR-278377 0.46 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L2 protein Q70SY1 UNIPROT up-regulates 9606 17178827 f miannu Although bbf2h7 protein is not expressed under normal conditions, it is markedly induced at the translational level during er stress, suggesting that bbf2h7 might contribute to only the late phase of unfolded protein response signaling. SIGNOR-151312 0.7 ADRA1A protein P35348 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256955 0.278 ATM protein Q13315 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by destabilization phosphorylation Thr134 SRAAFSHtQVIELER 9606 BTO:0002181 23890999 t miannu ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction. SIGNOR-276499 0.362 PI3K complex SIGNOR-C156 SIGNOR PIK3CG protein P48736 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252721 0.602 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10611223 t lperfetto Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau. SIGNOR-73533 0.335 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 10428798 t lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-217284 0.419 COL4A3 protein Q01955 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-253244 0.454 SARS1 protein P49591 UNIPROT tRNA(Ser) smallmolecule CHEBI:29179 ChEBI down-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270493 0.8 DAPK1 protein P53355 UNIPROT PELI1 protein Q96FA3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser39 GDRGRRKsRFALFKR 9606 BTO:0003575 33052227 t miannu DAPK1, which directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and turnover. SIGNOR-277531 0.2 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 0.2 CDK1 protein P06493 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 SIGNOR-C17 20150555 t gcesareni Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis. SIGNOR-163738 0.463 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270883 0.573 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272507 0.2 NDN protein Q99608 UNIPROT EID1 protein Q9Y6B2 UNIPROT up-regulates activity binding 10090 BTO:0000165 18557765 t llicata The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation. SIGNOR-237614 0.375 SEC61B protein P60468 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-265277 0.909 DHCR7 protein Q9UBM7 UNIPROT cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI down-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-267251 0.8 methylnaltrexone chemical CHEBI:136007 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10030 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258148 0.8 RARA protein P10276 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10772826 f lperfetto Retinoic acid and its receptors repress the expression and transactivation functions of nur77 SIGNOR-76980 0.291 Prolactin-releasing peptide-20 smallmolecule CHEBI:80301 ChEBI PRLHR protein P49683 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-257566 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 18682241 t flangone We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity. SIGNOR-242052 0.438 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-268111 0.8 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by destabilization phosphorylation Thr367 NNSSRPStPTINVLE 10090 BTO:0000165 28067271 t Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372 SIGNOR-255663 0.372 ESR2 protein Q92731 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268547 0.476 BRCA1 protein P38398 UNIPROT FOXC2 protein Q99958 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 22120723 f miannu We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. SIGNOR-253760 0.26 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276263 0.353 MAML1 protein Q92585 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. SIGNOR-84835 0.808 ALG2 protein Q9H553 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 t lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. SIGNOR-260419 0.8 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser567 SSSRRRRsSSTAPPT 9606 16513649 t llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization SIGNOR-145032 0.2 TADA2B protein Q86TJ2 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-269571 0.77 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 0.377 PABPC1 protein P11940 UNIPROT EIF4E protein P06730 UNIPROT 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-260968 0.805 PTPRA protein P18433 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI SIGNOR-248436 0.3 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259222 0.8 CSNK2A1 protein P68400 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 7598724 t llicata We report that recombinant glia maturation factor (GMF), a 17-kD brain protein, can be phosphorylated in vitro at the serine residue by protein kinase C (PKC), protein kinase A (PKA), and casein kinase II (CKII), and at the threonine residue by p90 ribosomal S6 kinase (RSK).  SIGNOR-250868 0.331 PRKACA protein P17612 UNIPROT SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1445 PSPTSRQsPASPPPL 9606 BTO:0000007 20622900 t miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. SIGNOR-263066 0.25 SRC protein P12931 UNIPROT DMAP1 protein Q9NPF5 UNIPROT down-regulates activity phosphorylation Tyr246 EQVAEEEyLLQELRK 9606 30553276 t miannu C-Src phosphorylates DMAP1 at Tyr246 and disrupts Bub3/DMAP1 complex formation. SIGNOR-279431 0.2 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 0.447 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 t CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. SIGNOR-251161 0.77 ILK protein Q13418 UNIPROT SYNPO2 protein Q9UMS6 UNIPROT up-regulates activity phosphorylation 9606 21643011 t miannu Fourth, ILK dependent phosphorylation of myopodin is found both in vivo and in vitro.|The ILK dependent activation of myopodin provides a novel link between extracellular matrix-integrin-ILK signaling and myopodin tumor suppression. SIGNOR-279622 0.503 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262755 0.336 FFAR2 protein O15552 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256803 0.2 MAGEL2 protein Q9UJ55 UNIPROT WASHC1 protein A8K0Z3 UNIPROT up-regulates activity binding 9606 23452853 t miannu Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport. SIGNOR-253515 0.2 CSAG2 protein Q9Y5P2 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity binding 9606 32761762 t miannu Here, we show that the previously undescribed CSAG2 protein is a direct activator of SIRT1.  Biochemical studies revealed that CSAG2 directly binds to and stimulates SIRT1 activity toward multiple substrates. Importantly, CSAG2 enhances SIRT1‐mediated deacetylation of p53, inhibits p53 transcriptional activity, and improves cell survival in response to genotoxic stress. SIGNOR-261670 0.2 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 10116 BTO:0000452 1749429 t lperfetto Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation. SIGNOR-236686 0.5 ITK protein Q08881 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity phosphorylation 9606 23454662 t miannu This ability of Itk to phosphorylate Galpha13 was abolished in Itk mutants R29C (no longer able to interact with the membrane, and thus unable to interact with Galpha13) and K391M (no kinase activity) (XREF_FIG).|To determine whether Itk is a downstream mediator of Galpha13, we examined whether Galpha13 could interact with Itk when locked in the GDP bound or GTP bound state. SIGNOR-279623 0.2 CDKL5 protein O76039 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 10090 23651931 t gcesareni This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293.| The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis SIGNOR-245881 0.36 PTPRF protein P10586 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance SIGNOR-264090 0.7 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser485 QPDNSSDsDYDLHGA 9606 9834084 t lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) SIGNOR-62311 0.342 OGT protein O15294 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity glycosylation Ser530 VVIPATVsNNVPGSD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267584 0.346 SNRPE protein P62304 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270681 0.944 CCL3 protein P10147 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 10090 15075201 t lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. SIGNOR-251723 0.555 CASP8 protein Q14790 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp348 GTGGLEPdLARGRWA 9606 BTO:0005111 32122970 t miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. SIGNOR-272194 0.315 RNF180 protein Q86T96 UNIPROT ZIC2 protein O95409 UNIPROT down-regulates quantity by destabilization ubiquitination 10116 18363970 t miannu Rinescan directly interact with Zic2. the ubiquitination of endogenous Zic2 was enhanced by Myc-Rines in rat neural stem cellline MNS70 cells. Rines-induced degradation of Zic2 SIGNOR-226303 0.374 RPL35A protein P18077 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262465 0.856 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257982 0.8 TRAF6 protein Q9Y4K3 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity ubiquitination 9606 23911927 t miannu Together, these results demonstrate that mTOR polyubiquitination by TRAF6 modulates its activation in response to amino acids and point to a role for K63 ubiquitin modification as a sensor of nutrient status. SIGNOR-278789 0.438 SMAD7 protein O15105 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 t lperfetto The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling SIGNOR-153917 0.569 CNR1 protein P21554 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates activity binding 9606 29751001 t miannu Another example is the heteromer between CB1 and orexin 1 receptor (OX1R). The CB1 activation potentiated the OX1R signaling (218), suggesting the interaction of these two receptors. Interaction of their surface distribution was also reported.  SIGNOR-264269 0.388 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 0.463 bortezomib chemical CHEBI:52717 ChEBI PSMD1 protein Q99460 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 t miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. SIGNOR-259312 0.8 CTBP1 protein Q13363 UNIPROT ZEB2 protein O60315 UNIPROT up-regulates activity binding 9606 16061479 t miannu Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP SIGNOR-225484 0.474 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. SIGNOR-236656 0.935 RAF1 protein P04049 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276407 0.2 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 t miannu Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA SIGNOR-250017 0.308 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-256185 0.9 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887;BTO:0001103 12058061 t lperfetto Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. SIGNOR-236575 0.51 CASP3 protein P42574 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261756 0.454 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248796 0.515 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 0.488 PPP3CA protein Q08209 UNIPROT FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t gcesareni We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells SIGNOR-143979 0.259 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 0.787 MAPK9 protein P45984 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. SIGNOR-178934 0.2 TP53 protein P04637 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 t miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 SIGNOR-253638 0.47 CDK5 protein Q00535 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr75 RPNPCAYtPPSLKAV 10116 BTO:0000142 10604473 t llicata We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. SIGNOR-250671 0.777 HSP90AB1 protein P08238 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10944114 t gcesareni The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex. SIGNOR-81043 0.388 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser718 KEAEEESsEDD 9606 BTO:0000007 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250860 0.386 CDK2 protein P24941 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by destabilization phosphorylation Thr156 HLFTFPPtPPKDVSP 9606 BTO:0000567 24820417 t miannu Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. SIGNOR-276634 0.362 SP3 protein Q02447 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 t lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. SIGNOR-251741 0.2 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-252683 0.45 CAMK1 protein Q14012 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD -1 8663317 t llicata Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site. SIGNOR-250611 0.512 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 0.8 ANK3 protein Q12955 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity binding 10090 BTO:0003102 30504823 t miannu Importantly, the 480 kDa ankyrin-G isoform has also been shown to stabilize GABAergic synapses on the soma and AIS of excitatory pyramidal neurons by interacting with the GABAA receptor-associated protein (GABARAP) to inhibit GABAA receptor endocytosis SIGNOR-266709 0.445 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt SIGNOR-252448 0.642 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 10551811 t gcesareni The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-72108 0.359 CCKAR protein P32238 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257236 0.252 BCL7A protein Q4VC05 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269784 0.49 AFDN protein P55196 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220917 0.2 CDH2 protein P19022 UNIPROT CDON protein Q4KMG0 UNIPROT up-regulates binding 9606 SIGNOR-C21 20160094 t gcesareni We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner SIGNOR-163844 0.648 PDCD1 protein Q15116 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 BTO:0000782 22740686 f Barakat MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 SIGNOR-275411 0.262 CDK1 protein P06493 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates activity phosphorylation Thr383 HESCGQCtPCREGVD 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275594 0.2 STARD8 protein Q92502 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-260519 0.557 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260881 0.2 DTX1 protein Q86Y01 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-254317 0.781 SYVN1 protein Q86TM6 UNIPROT HMGCR protein P04035 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 14593114 t miannu In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols. SIGNOR-272594 0.562 BRCA1-C complex complex SIGNOR-C299 SIGNOR G2/M_transition-checkpoint phenotype SIGNOR-PH146 SIGNOR up-regulates 9606 BTO:0000567 16391231 f lperfetto This result implies that the BRCA1/BARD1–RMN–CtIP complex is required for activation of the G2/M checkpoint. SIGNOR-263229 0.7 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 t Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation SIGNOR-255828 0.357 NCS1 protein P62166 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity 10116 21104311 f miannu In chromaffin and PC12 cells, NCS-1 can enhance secretion via its activation of PI4 kinaseIIIb with the subsequent increase in PIP2 levels. PIP2 has been shown to be an important requirement for exocytosis SIGNOR-263963 0.649 RUNX1 protein Q01196 UNIPROT MECOM protein Q03112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22689058 f irozzo Our results suggest that RUNX1 and EVI1 could be regulating each other. RUNX1 would activate EVI1 transcription, and when highly expressed, EVI1 could bind to RUNX1 at protein level, inhibiting its activity as a transcription factor, acting in a negative feedback. SIGNOR-255715 0.524 PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity dephosphorylation 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-254119 0.412 ATM protein Q13315 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser106 GPGQVMAsQAQQSSP 9606 20471956 t lperfetto Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage SIGNOR-165567 0.4 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Thr356 FREFCIPtSSNIEQQ 9606 BTO:0000007 12123746 t gcesareni These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells SIGNOR-247782 0.2 LIMK2 protein P53671 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates activity phosphorylation 9606 32859889 t miannu In vitro kinase assays revealed that LIMK2 phosphorylates SRPK1 (Fig. xref ).|LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1. SIGNOR-279625 0.2 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 0.373 LRRK1 protein Q38SD2 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity phosphorylation 9606 27600824 t miannu In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment.|Lrrk1 phosphorylates and activates RAC1 and Cdc42 small GTPase proteins in osteoclasts. SIGNOR-279626 0.292 Naltriben chemical CID:5486827 PUBCHEM OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258425 0.8 sitagliptin chemical CHEBI:40237 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 20927248 t Luana Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor SIGNOR-257883 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 22369944 t lperfetto Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-217316 0.337 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1616 NSHSPAGsAAISQQD 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275611 0.258 zotepine chemical CHEBI:32316 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 20223878 t Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. SIGNOR-257829 0.8 TBK1 protein Q9UHD2 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 BTO:0000801 22921120 t llicata Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance. SIGNOR-191944 0.709 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 0.344 KDM5C protein P41229 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264305 0.2 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity binding 9606 BTO:0000007 28195531 t While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. SIGNOR-252029 0.424 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 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-127908 0.788 EIF2B2 protein P49770 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-269130 0.751 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Ser229 VKIYSSNsGPTRRED 9606 BTO:0000672 15793569 t llicata In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues. SIGNOR-134851 0.656 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 0.604 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 0.754 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 0.278 POU5F1 protein Q01860 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254933 0.559 PAH protein P00439 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-263989 0.8 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276312 0.502 CFH protein P08603 UNIPROT CFB protein P00751 UNIPROT down-regulates activity binding 9606 19050261 t miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) SIGNOR-252142 0.518 NMUR1 protein Q9HB89 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256751 0.492 TPSAB1 protein Q15661 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity binding 10116 21999702 t lperfetto Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2).|Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2. SIGNOR-251744 0.251 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248788 0.431 TALDO1 protein P37837 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267090 0.8 ASXL3 protein Q9C0F0 UNIPROT CBX5 protein P45973 UNIPROT down-regulates activity binding 9606 BTO:0000972 25450400 t miannu Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. SIGNOR-266763 0.251 CDKN2A protein P42771 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 SIGNOR-C18 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks, cdk4 and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44554 0.905 PRSS2 protein P07478 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-263606 0.2 LATS2 protein Q9NRM7 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation -1 24157836 t miannu FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. SIGNOR-272138 0.528 PPP2CB protein P62714 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 8650155 t gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity SIGNOR-42123 0.481 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT up-regulates activity phosphorylation Ser403 QRSRGRAsSHSSQTQ -1 7925482 t lperfetto Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence. SIGNOR-248903 0.362 BTRC protein Q9Y297 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 16421275 t lperfetto Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein SIGNOR-235631 0.664 MAP3K7 protein O43318 UNIPROT NLK protein Q9UBE8 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12482967 t gcesareni The tak1-nlk-mapk-related pathway antagonizes signalling between beta-catenin and transcription factor tcf. SIGNOR-96425 0.651 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity binding 9606 BTO:0000567 14565952 t llicata MKL2 binds to and activates SRF similar to myocardin and MKL1. SIGNOR-237671 0.2 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134529 0.745 ADNP protein Q9H2P0 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 32533114 t miannu Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. SIGNOR-266756 0.249 WNT10B protein O00744 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131625 0.617 CAPRIN1 protein Q14444 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 17210633 t SARA Caprin-1 and G3BP-1 were directly or indirectly associated in a stable complex. The Caprin-1/G3BP-1 complex occurs in cytoplasmic RNA granules SIGNOR-260982 0.588 AKT1 protein P31749 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT down-regulates quantity by destabilization phosphorylation Thr181 LIRDRLKtEPFEENS 9606 BTO:0000567 25661488 t miannu Akt1 phosphorylates XLF at T181 Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3β leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(β-TRCP) in a CKI-dependent manner.  SIGNOR-276881 0.358 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2I protein P63279 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271312 0.532 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC13 protein Q99880 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-271995 0.2 proline smallmolecule CHEBI:26271 ChEBI Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270434 0.8 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248679 0.629 MAPK1 protein P28482 UNIPROT 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-200880 0.309 MAP4K1 protein Q92918 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273899 0.2 PTPN1 protein P18031 UNIPROT EPHA3 protein P29320 UNIPROT down-regulates activity dephosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 21135139 t Nevertheless, the finding that phosphorylation of the activation loop tyrosine (EphA3-Y779), a recently identified PTP1B substrate (Mertins et al., 2008), is essential for ligand-induced endocytosis (Janes et al., 2009) SIGNOR-248426 0.417 PHLPP1 protein O60346 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248330 0.648 CDK7 protein P50613 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG 9606 BTO:0001086 31306665 t lperfetto Here, we combined molecular and cellular biology with CRISPR/Cas9-mediated genome engineering to pinpoint the function of serine 12 of OCT4 in ESCs. Using chemical inhibitors and an antibody specific to OCT4 phosphorylated on S12, we identified cyclin-dependent kinase (CDK) 7 as upstream kinase. |Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2. SIGNOR-264404 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263124 0.7 GPC6 protein Q9Y625 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates activity binding 9606 31756413 t miannu Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. SIGNOR-264031 0.35 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 SIGNOR-C9 15241418 t llicata We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase SIGNOR-126748 0.746 JUN protein P05412 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254874 0.27 FGFR4 protein P22455 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251142 0.402 PKA proteinfamily SIGNOR-PF17 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1548 YAPSRRMtSVATAKG -1 21406690 t miannu PKA phosphorylated LRP6, which enhanced the binding of Gα(s) to LRP6, its localization to the plasma membrane, and the production of cAMP in response to PTH. Only alteration of Thr1548 abolished the phosphorylation of LRP6C by PKA (Fig. 6B), and mass spectrometry analysis confirmed that Thr1548 was the PKA phosphorylation site in LRP6C (fig. S1). SIGNOR-275416 0.2 ACOT4 protein Q8N9L9 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271807 0.8 DLL4 protein Q9NR61 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209744 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203604 0.777 WDFY3 protein Q8IZQ1 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 22653340 f miannu ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. SIGNOR-266794 0.7 MAP3K2 protein Q9Y2U5 UNIPROT STK38 protein Q15208 UNIPROT up-regulates quantity by stabilization phosphorylation Ser91 LGLEDFEsLKVIGRG 9606 31690749 t miannu Our data suggest that Ser91 phosphorylation of STK38 by MEKK2 possibly blocks the interaction of calpain with STK38 or disrupts proper conformation for cleaving, thereby protecting STK38 from calpain-dependent degradation. SIGNOR-279066 0.402 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates activity binding 9606 BTO:0001487 18940940 t fspada Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity. SIGNOR-236936 0.914 PRKCA protein P17252 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 t miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. SIGNOR-276459 0.2 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation SIGNOR-129308 0.312 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 t gcesareni Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-158624 0.697 PDX1 protein P52945 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 t In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. SIGNOR-255541 0.643 CYLD protein Q9NQC7 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity deubiquitination 10090 29291351 t gianni Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. SIGNOR-266437 0.636 GRIN2B protein Q13224 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264123 0.729 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268607 0.261 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120140 0.311 MBD1 protein Q9UIS9 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 f Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. SIGNOR-254030 0.2 PRKACA protein P17612 UNIPROT ARPP21 protein Q9UBL0 UNIPROT up-regulates activity phosphorylation Ser58 QERRKSKsGAGKGKL -1 10854908 t miannu The specificity of antibody G534 was examined using recombinant full-length rat ARPP-21 phosphorylated by PKA. Radiolabeled ARPP-21 from a reaction containing [γ32P]ATP correlated with the detection of phospho-Ser55-ARPP-21 by immunoblotting (Fig. 1A, left and middle panels). SIGNOR-263107 0.2 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser117 SFSLEEKsKISKNRV 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166321 0.361 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17548584 t svumbaca The loss of macrophage expression of HIF-1 led to significant decreases in the production of TNF-a, IL-1a, IL-1b, and IL-12 SIGNOR-256235 0.336 IL1A protein P01583 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 19005488 f miannu UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. SIGNOR-252209 0.492 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser1073 PPLQRGKsQQLTVSA -1 14970204 t miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII SIGNOR-262687 0.429 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 t Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256255 0.687 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-252948 0.692 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression 9606 10922362 f miannu We demonstrate a new target gene for upr-induced transcription, herp. SIGNOR-80156 0.7 SGO1 protein Q5FBB7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000567 24055156 t lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. SIGNOR-265264 0.2 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser242 SSLRASTsKSESSQK -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-250234 0.309 HNF1B protein P35680 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity binding 9606 BTO:0000007 9671480 t 2 miannu The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays. SIGNOR-241323 0.373 RPS6KB1 protein P23443 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 11500364 t lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity SIGNOR-109712 0.736 GRK2 protein P25098 UNIPROT SNCG protein O76070 UNIPROT down-regulates activity phosphorylation Ser124 EVAEEAQsGGD -1 10852916 t GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser124 dramatically inhibits γ-synuclein phosphorylation by GRK2 SIGNOR-251204 0.2 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser374 GLEQAILsPGQNSGN 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198988 0.322 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist SIGNOR-260248 0.2 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 16291744 t gcesareni Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase. SIGNOR-141634 0.335 RNF7 protein Q9UBF6 UNIPROT NF1 protein P21359 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271453 0.249 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270407 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR YY1 protein P25490 UNIPROT up-regulates activity acetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268834 0.652 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257967 0.8 SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14522994 t lperfetto Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor SIGNOR-118407 0.795 PHGDH protein O43175 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates activity chemical modification 9606 25406093 t lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. SIGNOR-268567 0.8 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 0.2 SH3GL2 protein Q99962 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263883 0.7 EPHB2 protein P29323 UNIPROT ARHGEF15 protein O94989 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr353 PLQDEPLyQTYRAAV 9606 BTO:0000007 21029865 t miannu We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361 SIGNOR-262864 0.485 DRAM2 protein Q6UX65 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259144 0.2 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276120 0.711 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7834749 t Nuclear p53 amattioni Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis SIGNOR-33922 0.753 ACIN1 protein Q9UKV3 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 10490026 f Cleaved by CASP3 amattioni Acinus induces apoptotic chromatin condensation after cleavage by caspase-3 without inducing dna fragmentation. SIGNOR-70797 0.7 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268070 0.8 SYN3 protein O14994 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269183 0.2 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr420 RLIEDNEyTARQGAK -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251167 0.2 FBXW11 protein Q9UKB1 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates ubiquitination 9606 11359933 t gcesareni Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3. SIGNOR-108240 0.261 F2RL3 protein Q96RI0 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256772 0.323 LYN protein P07948 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9534 11514608 t BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain. SIGNOR-251403 0.381 PTPN11 protein Q06124 UNIPROT FGFR2 protein P21802 UNIPROT down-regulates activity dephosphorylation 9606 23420874 t miannu In forming this heterotetrameric complex Grb2 inhibits both the dephosphorylation of FGFR2 by Shp2 and the phosphorylation of Shp2 by FGFR2 (XREF_FIG, respectively).|Knockdown of Grb2 elevates Shp2 phosphorylation (XREF_FIG), strongly suggesting that the inability of Shp2 to interact directly with the receptor in the presence of Grb2 prevents FGFR2 kinase activity toward Shp2. SIGNOR-277030 0.622 PI3K complex SIGNOR-C156 SIGNOR PIK3CD protein O00329 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252720 0.623 Naltrindole chemical CHEBI:81528 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258818 0.8 FOXP1 protein Q9H334 UNIPROT CSF1R protein P07333 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000738 15286807 t Gianni Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. SIGNOR-269048 0.296 RPL35 protein P42766 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262466 0.863 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 t amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. SIGNOR-85183 0.341 EDNRA protein P25101 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257427 0.471 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNT3 protein P45378 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136942 0.306 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr471 PIKPLIStPPVSSQP 9606 BTO:0000567 30021153 t lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. SIGNOR-265034 0.2 LAT protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246060 0.808 SSTR3 protein P32745 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256820 0.452 CYP21A2 protein P08686 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI down-regulates quantity chemical modification 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-268646 0.8 perifosine chemical CHEBI:67272 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 BTO:0001130 14617782 t Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.| Our results demonstrate that Akt is an important cellular target of perifosine action. In addition, these studies show that the membrane translocation of certain PH domain-containing molecules can be greatly perturbed by the alkylphospholipid class of drugs and imply further that the PI3K/Akt pathway contributes to regulation of p21(WAF1/CIP1) expression. SIGNOR-119189 0.8 lenvatinib chemical CHEBI:85994 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191454 0.8 CBL protein P22681 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19450681 t lperfetto Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation SIGNOR-185680 0.732 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg25 PLLSARTrARRPESK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263568 0.887 PPP2R2C protein Q9Y2T4 UNIPROT SRC protein P12931 UNIPROT down-regulates activity binding 9606 BTO:0001938 18069897 t gcesareni We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC SIGNOR-247966 0.2 WDR83 protein Q9BRX9 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15118098 t gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. SIGNOR-124476 0.525 TOP2A protein P11388 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 20562910 f lperfetto Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis. SIGNOR-242530 0.7 FOXL2 protein P58012 UNIPROT STAR protein P49675 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254180 0.36 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 0.8 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 0.87 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser339 SPISTPTsPGSLRKH 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250673 0.405 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle SIGNOR-237039 0.328 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250875 0.379 CAPN3 protein P20807 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251602 0.323 MAPKAPK2 protein P49137 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15688025 t gcesareni Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53. SIGNOR-133560 0.364 MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni Hpk1 binds and phosphorylates mekk1 directly, SIGNOR-43996 0.455 progesterone smallmolecule CHEBI:17026 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268649 0.8 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 0.2 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188781 0.516 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257963 0.8 RASGRF2 protein O14827 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260575 0.554 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-67634 0.716 STAT1 protein P42224 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19643666 t lperfetto Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways. SIGNOR-249565 0.677 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250290 0.674 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation 9606 10487978 t miannu Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267411 0.432 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-235964 0.755 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1064 SCPIKEDsFLQRYSS 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250619 0.371 HIF-1 complex complex SIGNOR-C418 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity transcriptional regulation 10116 11120745 t Collectively these results indicate that H-Ras up-regulates the glut1 promoter, at least in part, by increasing HIF-1alpha protein levels leading to transactivation of promoter through the HIF-1 binding site. SIGNOR-267478 0.411 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 0.778 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. SIGNOR-203306 0.2 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 0.7 SLC16A4 protein O15374 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. SIGNOR-242519 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop SIGNOR-249652 0.531 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr274 SNVVRKDyDTLSKCS -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263039 0.389 PRKCH protein P24723 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276014 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR HIRA protein P54198 UNIPROT up-regulates phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 11238922 t lperfetto Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle. SIGNOR-216670 0.326 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 0.92 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12217858 t gcesareni Addition of active c-src and [32p]atp to the purified romk1 protein resulted in the phosphorylation of the romk1 protein. However, c-src did not phosphorylate r1y337a in which tyrosine residue 337 was mutated to alanine. Furthermore, phosphopeptide mapping identified two phosphopeptides from the trypsin-digested romk1 protein. SIGNOR-92513 0.312 AP-2 complex complex SIGNOR-C245 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR down-regulates quantity relocalization 9606 BTO:0000938 25600368 t miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. SIGNOR-264990 0.2 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Ser245 GGGDLPNsQEALQKL 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275648 0.2 TFEB protein P19484 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants SIGNOR-276551 0.325 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249247 0.29 RPGRIP1L protein Q68CZ1 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163320 0.2 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser673 RVQSKIGsLDNITHV -1 12435421 t miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly SIGNOR-250007 0.433 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1206 SHSFRGAyGLAMKVA 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187847 0.408 Sincalide smallmolecule CID:9833444 PUBCHEM CCKAR protein P32238 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257466 0.8 HSP90AA1 protein P07900 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 18591668 t lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. SIGNOR-179268 0.415 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 0.69 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268598 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-233438 0.614 NR3C1 protein P04150 UNIPROT LCK protein P06239 UNIPROT up-regulates binding 9606 16888650 t gcesareni The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. SIGNOR-251685 0.355 IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000801 20717897 t lperfetto The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation. SIGNOR-167524 0.484 GPR84 protein Q9NQS5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256983 0.25 AKT1 protein P31749 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 t gcesareni Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b. SIGNOR-252520 0.393 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.748 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT down-regulates activity sumoylation Lys417 TSPVTQkVkDEAAAQP 9606 16442531 t We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. SIGNOR-256130 0.367 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg707 ESTVMATrKMHDRLE -1 10026263 t lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 SIGNOR-263647 0.499 HLA1 proteinfamily SIGNOR-PF87 SIGNOR Class I MHC complex SIGNOR-C425 SIGNOR form complex binding -1 28367149 t scontino One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER) SIGNOR-267776 0.966 ABL1 protein P00519 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr508 EDMRGILyAAPQLRS 10090 11120811 t gcesareni The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl. SIGNOR-245283 0.533 PER2 protein O15055 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267977 0.762 GNG2 protein P59768 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199138 0.2 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 0.2 STAT6 protein P42226 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates 9606 BTO:0000018 12517954 f lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. SIGNOR-254101 0.328 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259441 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. SIGNOR-252766 0.2 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268205 0.8 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248749 0.738 FBXW7 protein Q969H0 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 t miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 SIGNOR-254774 0.327 GATA3 protein P23771 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 12876556 f Initiation of transcription of the gene encoding IL-4 in naive T(H) cells is regulated by the T(H) 2-specific transcription factor GATA3 SIGNOR-254500 0.487 LZTR1 protein Q8N653 UNIPROT KRAS protein P01116 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 31337872 t Gianni We demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling. SIGNOR-269069 0.25 CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.827 MAOA protein P21397 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264001 0.8 PRKCB protein P05771 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t lperfetto Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization SIGNOR-151011 0.2 LMX1A protein Q8TE12 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 BTO:0000007 9452425 t lperfetto Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. SIGNOR-236812 0.339 MECOM protein Q03112 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15889140 t Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  SIGNOR-266060 0.2 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr814 PLHDGSRtPAQSGAW 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143943 0.776 MAPK1 protein P28482 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr693 RELVEPLtPSGEAPN -1 1651322 t lperfetto A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase SIGNOR-20545 0.639 peptide smallmolecule CHEBI:16670 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR up-regulates activity binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  SIGNOR-270815 0.8 PAX7 protein P23759 UNIPROT PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198635 0.304 CDK1 protein P06493 UNIPROT KIF20B protein Q96Q89 UNIPROT up-regulates activity phosphorylation Thr1644 VKHPGCTtPVTVKIP 9606 11470801 t miannu Here we report the identification of a novel KRP, termed KRMP1, which undergoes in vivo phosphorylation. The carboxyl-terminal globular tail domain is strongly phosphorylated by mitotic kinase activities almost attributed to cdc2 kinase, which is responsible for phosphorylation on residue Thr-1604 of KRMP1. SIGNOR-262695 0.41 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 0.36 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates phosphorylation Ser2733 SVSPKRNsISRTHKD 9606 15383279 t llicata Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to pkd activation in two ways: it recruits an upstream kinase pkceta and coordinates pka phosphorylation events that release activated protein kinase d. Thus, akap-lbc synchronizes pka and pkc activities in a manner that leads to the activation of a third kinase. SIGNOR-129345 0.332 GNAI1 protein P63096 UNIPROT PLD2 protein O14939 UNIPROT down-regulates binding 9606 9148895 t gcesareni The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi SIGNOR-48256 0.307 ORC1 protein Q13415 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267567 0.946 HECTD4 protein Q9Y4D8 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267146 0.2 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 t gcesareni Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor. SIGNOR-247770 0.2 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates dephosphorylation 9606 22080863 t gcesareni We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._ SIGNOR-177116 0.72 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 21757781 t gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian ta rget of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. SIGNOR-174886 0.8 MMUT protein P22033 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 1978672 t miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). SIGNOR-269109 0.8 FN1 protein P02751 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity binding 9606 23290138 t apalma Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells. SIGNOR-255846 0.711 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp SIGNOR-199180 0.2 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23287467 t miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. SIGNOR-272896 0.877 PKNOX1 protein P55347 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 9482740 t 2 miannu we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target. SIGNOR-241215 0.613 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-59157 0.752 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser533 KKSQHRSsSSAPHHN 10441130 t miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation SIGNOR-250340 0.43 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 0.2 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269240 0.462 UBTF protein P17480 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 15970593 t lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. SIGNOR-269568 0.506 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 0.347 TBX2 protein Q13207 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249593 0.345 GSK3A protein P49840 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 BTO:0000567 16543145 t  MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein SIGNOR-251217 0.457 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159435 0.26 IKBKE protein Q14164 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser556 EREAIRLsLEQALPP 9606 BTO:0002181 30472208 t miannu Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS. SIGNOR-277618 0.283 STAP1 protein Q9ULZ2 UNIPROT TEC protein P42680 UNIPROT up-regulates activity binding 9606 BTO:0000007 10518561 t miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction. SIGNOR-261819 0.392 GNAI2 protein P04899 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-267849 0.634 ITGB1BP1 protein O14713 UNIPROT ITGB6 protein P18564 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257662 0.287 PTMS protein P20962 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates activity binding 9606 BTO:0000567 16150697 t miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells. SIGNOR-268462 0.2 SPAG5 protein Q96R06 UNIPROT CENPE protein Q02224 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-252041 0.379 WWP2 protein O00308 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 19651900 t lperfetto The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination|AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death. SIGNOR-268849 0.372 PTPN5 protein P54829 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000938 BTO:0000671 11983687 t lperfetto Wild-type step(61) dephosphorylates fyn at tyr(420) but not at tyr(531). These results suggest that step regulates the activity of fyn by specifically dephosphorylating the regulatory tyr(420) and may be one mechanism by which fyn activity is decreased within psds. SIGNOR-86791 0.527 CAV1 protein Q03135 UNIPROT SLC1A2 protein P43004 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 t miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. SIGNOR-264809 0.248 CHUK protein O15111 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 16103118 t gcesareni Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286. SIGNOR-139570 0.379 BMX protein P51813 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity phosphorylation Tyr12 NVLAKALyDNVAESP 10090 BTO:0002572 21937722 t miannu Recombinant Bmx kinase was found to effectively phosphorylate the wt CAS SH3 domain on Tyr-12 (Figure 2B). A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells.  SIGNOR-276384 0.506 CCT5 protein P48643 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272861 0.755 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 0.674 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 0.779 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes SIGNOR-260440 0.7 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249089 0.43 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65277 0.442 ATF4 protein P18848 UNIPROT DARS2 protein Q6PI48 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-269418 0.2 QRICH1 protein Q2TAL8 UNIPROT TARS2 protein Q9BW92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269407 0.2 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser539 LTAQRRAsTVSSVTQ -1 15684429 t miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. SIGNOR-263018 0.249 HES1 protein Q14469 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265146 0.441 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser2 sDNDDIEV 9606 8018564 t gcesareni Here, we have mapped the nh2-terminal in vivo phosphorylation sites of max to ser2 and ser11[...] SIGNOR-35772 0.361 CDH6 protein P55285 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265868 0.578 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 17466630 t gcesareni Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-154626 0.429 PPP2CB protein P62714 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP 9606 16596250 t Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. SIGNOR-248582 0.309 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 11483655 t lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src and Fyn and compared this to phosphorylation by tyrosine kinases associated with the postsynaptic density (PSD)|Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases SIGNOR-249338 0.768 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 0.7 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 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-203499 0.448 glycine smallmolecule CHEBI:15428 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268237 0.8 fenoterol chemical CHEBI:149226 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  SIGNOR-257868 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264953 0.7 RETREG3 protein Q86VR2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261490 0.7 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr136 SEEGYQDyEPEA 9606 BTO:0000975;BTO:0000142 11744621 t llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. SIGNOR-113069 0.532 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation 9606 7816602 t inferred from 70% family members lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-270105 0.2 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser418 VEEDPLNsGDDVSEQ -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250993 0.414 CDK1 protein P06493 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. SIGNOR-151799 0.575 CSNK2A1 protein P68400 UNIPROT SEPTIN2 protein Q15019 UNIPROT down-regulates phosphorylation Ser218 YHLPDAEsDEDEDFK 9606 16857012 t lperfetto Here we show that human septin 2 is phosphorylated in vivo at ser218 by casein kinase ii. Septin 2 binds and hydrolyses gtp. The purified protein has the capacity to polymerize into long filaments when loaded with gtp or gdp. Moreover, we show that the endogenous protein in hela cells, like that produced in insect cells, is phosphorylated by casein kinase ii and that this phosphorylation alters nucleotide binding. SIGNOR-148010 0.2 CSNK1A1 protein P48729 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Ser269 QVRVGGSsVDLHRFH 9606 24412065 t miannu Moreover, CK1α phosphorylates p120-catenin on Ser268 and Ser269, releasing this protein from the signalosome and facilitating the subsequent phosphorylation of cadherin and the disruption of this cadherin interaction with LRP5/6 SIGNOR-277893 0.2 NLGN2 protein Q8NFZ4 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264977 0.7 AKT2 protein P31751 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation 9606 16023596 t gcesareni Activated pi3k/akt pathway results in inhibitory phosphorylation of gsk3 SIGNOR-138179 0.557 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261451 0.265 CYP17A1 protein P05093 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268657 0.8 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization phosphorylation Ser337 ASGTLPVsQPKSWAS 9606 BTO:0001109 20096447 t miannu The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.  SIGNOR-276276 0.252 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 9606 BTO:0000568 10747897 t llicata Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities. SIGNOR-250967 0.668 CDK5RAP2 protein Q96SN8 UNIPROT CEP63 protein Q96MT8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271722 0.692 JAK1 protein P23458 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity phosphorylation Tyr619 NKVDDCNyAIKRIRL 10090 BTO:0000099 25113558 t miannu JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3. SIGNOR-276677 0.2 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 0.628 PDP2 protein Q9P2J9 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation 9606 20208177 t Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation SIGNOR-251665 0.658 CKM complex complex SIGNOR-C406 SIGNOR Core mediator complex complex SIGNOR-C405 SIGNOR down-regulates activity binding -1 23563140 t miannu We found that interaction of the CKM with Mediator's middle module interferes with CTD-dependent RNAPII binding to a previously unknown middle-module CTD-binding site and with the holoenzyme formation process. Taken together, our results reveal the basis for CKM repression, clarify the origin of the connection between CKM subunits and the CTD and suggest that a combination of competitive interactions and conformational changes that facilitate holoenzyme formation underlie the mechanism of transcription regulation by Mediator. SIGNOR-266687 0.763 MAPK3 protein P27361 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity phosphorylation Thr906 SLDNNYStPNERGDH 9615 BTO:0000837 32010791 t miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. SIGNOR-277506 0.293 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 0.2 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 0.8 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 BTO:0002181 15988018 t lperfetto In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif. SIGNOR-138428 0.2 ASIP protein P42127 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-268698 0.739 monoisononyl phthalate chemical CHEBI:132593 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268779 0.8 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 0.425 MAX protein P61244 UNIPROT MGA protein Q8IWI9 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240261 0.57 AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t PI-3K/Akt-dependent manner. lperfetto We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-244271 0.2 clofarabine chemical CHEBI:681569 ChEBI RRM1 protein P23921 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate SIGNOR-258357 0.8 CDC7 protein O00311 UNIPROT RAD18 protein Q9NS91 UNIPROT unknown phosphorylation Ser434 IQEVLSSsESDSCNS 9606 21098111 t llicata Although the cdc7/rad18 interaction and phosphorylation at s434 are induced by dna damage, s434 was also observed to be phosphorylated basally SIGNOR-170049 0.489 USP6 protein P35125 UNIPROT MMP10 protein P09238 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-164943 0.2 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 0.573 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 10783894 t gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. SIGNOR-252928 0.2 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 0.435 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 0.2 AMPK complex SIGNOR-C15 SIGNOR PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 22137581 t lperfetto Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells. SIGNOR-216612 0.242 Papain-like proteinase protein P0C6X9-PRO_0000037340 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression 9606 BTO:0000007 17761676 f lperfetto SARS-CoV PLpro domain inhibits activation of IFN-β promoter following engagement of TLR3 or RIG-I pathways independent of its protease activity SIGNOR-260277 0.2 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 0.622 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp683 HHGVVEVdAAVTPEE -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261765 0.489 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 0.8 FOXA1 protein P55317 UNIPROT KRT7 protein P08729 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 20043065 f miannu These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. SIGNOR-254167 0.28 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates activity phosphorylation Ser551 CVMRFLVsKRKFKES 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-249209 0.324 OPRL1 protein P41146 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-257001 0.347 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 0.575 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-51292 0.458 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 0.316 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270403 0.8 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 0.396 MBD2 protein Q9UBB5 UNIPROT CHD4 protein Q14839 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000776 23071088 f lperfetto MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes SIGNOR-254102 0.632 porfimer chemical CHEBI:60652 ChEBI FCGR1A protein P12314 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000876 2544592 t miannu Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals. SIGNOR-259303 0.8 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 0.808 PPARA protein Q07869 UNIPROT CPT1A protein P50416 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 f miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. SIGNOR-255047 0.63 PHF5A protein Q7RTV0 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-268409 0.91 AIMP2 protein Q13155 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270361 0.921 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by destabilization phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 t gcesareni In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. SIGNOR-132971 0.904 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 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-147203 0.497 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT up-regulates activity phosphorylation Ser236 AKRRRLSsLRASTSK 10090 15809305 t lperfetto A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size. SIGNOR-135176 0.937 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). SIGNOR-59647 0.677 PER2 protein O15055 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 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-256370 0.7 dicyclomine chemical CHEBI:4514 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-258388 0.8 KLF2 protein Q9Y5W3 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15947087 f Regulation of expression miannu Our results show that KLF2 positively regulates the human (ε) and murine (Ey and βh1) embryonic globin genes at both E10.5 and E12.5, in the yolk sac, which is the site of primitive erythropoiesis. SIGNOR-251830 0.243 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201318 0.851 EGR1 protein P18146 UNIPROT TBXA2R protein P21731 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19747485 f Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein. SIGNOR-254253 0.26 DNMT3A protein Q9Y6K1 UNIPROT CDKN2C protein P42773 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-261508 0.339 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 11864573 t The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. SIGNOR-248530 0.39 RET protein P07949 UNIPROT DOK6 protein Q6PKX4 UNIPROT up-regulates binding 9606 BTO:0000671 15286081 t gcesareni These data identify dok-6 as a novel dok-4/5-related adaptor molecule that may function in vivo to transduce signals that regulate ret-mediated processes such as axonal projection. SIGNOR-127382 0.647 LEF1 protein Q9UJU2 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 24344199 t lperfetto We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression. SIGNOR-251722 0.28 RAB12 protein Q6IQ22 UNIPROT SLC36A4 protein Q6YBV0 UNIPROT down-regulates quantity by destabilization relocalization 10090 BTO:0002572 23478338 t lperfetto We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters. SIGNOR-264763 0.445 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 FGLSRLMtGDTYTAH 9606 10964922 t Manara We demonstrate here that autophosphorylation of ABL1 is intermolecular and stimulates Abl catalytic activity. SIGNOR-260781 0.2 MCHR1 protein Q99705 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257302 0.529 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 0.2 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120479 0.268 HBA1 protein P69905 UNIPROT APOB protein P04114 UNIPROT up-regulates quantity by stabilization 9606 8611031 f Regulation of binding miannu Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages SIGNOR-251755 0.319 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 0.342 PTPN1 protein P18031 UNIPROT IGF1R protein P08069 UNIPROT down-regulates activity dephosphorylation 9606 11884589 t lperfetto Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells. SIGNOR-115709 0.861 CSNK2A1 protein P68400 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser263 GEDTLSDsDDEDDEE -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-250921 0.446 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 0.362 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 0.424 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr334 RLFFVIEyVNGGDLM 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-111928 0.533 PNMT protein P11086 UNIPROT adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity chemical modification 9606 7961964 t brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). SIGNOR-264007 0.8 CyclinA2/CDK2 complex SIGNOR-C83 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-265046 0.514 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 0.7 XAF1 protein Q6GPH4 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates binding 9606 17613533 t gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3. SIGNOR-156843 0.415 KX2-391 chemical CID:23635314 PUBCHEM SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193624 0.8 EIF4E protein P06730 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30459806 f gianni The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation SIGNOR-268529 0.7 SKI protein P12755 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253300 0.781 PSMA5 protein P28066 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-263364 0.87 CSNK2A2 protein P19784 UNIPROT CDC37 protein Q16543 UNIPROT up-regulates activity phosphorylation Ser13 VWDHIEVsDDEDETH -1 12930845 t llicata Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site. SIGNOR-250982 0.489 MYC protein P01106 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates quantity by expression 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-267587 0.33 IL20 protein Q9NYY1 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 11163236 t gcesareni An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis. SIGNOR-151877 0.606 AKT proteinfamily SIGNOR-PF24 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates activity phosphorylation Ser87 FIFMRRSsLLSRSSS 9606 16282323 t lperfetto Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL). SIGNOR-141581 0.2 MXD1 protein Q05195 UNIPROT UBTF protein P17480 UNIPROT down-regulates quantity by repression 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-269646 0.36 CSNK1A1 protein P48729 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264877 0.2 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 0.8 serotonin smallmolecule CHEBI:28790 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264293 0.8 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT down-regulates activity phosphorylation Ser70 QNNSFQRsKRRYFKL 9534 15228384 t lperfetto The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain. SIGNOR-249266 0.366 TFEB protein P19484 UNIPROT HPS3 protein Q969F9 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276794 0.2 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 0.463 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 16440056 f lperfetto The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons. SIGNOR-265059 0.7 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 0.411 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7673243 t acerquone We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain. SIGNOR-30697 0.78 KDM6A protein O15550 UNIPROT ETV6 protein P41212 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-260032 0.3 RNA Polymerase III complex SIGNOR-C389 SIGNOR transfer RNA smallmolecule CHEBI:17843 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-266143 0.8 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 0.933 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 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-255037 0.845 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t gcesareni Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. SIGNOR-179109 0.85 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 0.458 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 30274374 f miannu AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. SIGNOR-260096 0.567 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 0.584 RAP1B protein P61224 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0003104 12808052 t lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. SIGNOR-253363 0.443 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 0.481 PRKCD protein Q05655 UNIPROT FGF1 protein P05230 UNIPROT up-regulates quantity phosphorylation Ser131 VGLKKNGsCKRGPRT 9606 24595027 t miannu Translocated FGF1 can be phosphorylated by PKC\u03b4 on serine 130. SIGNOR-278451 0.2 NEDD4L protein Q96PU5 UNIPROT SCN5A protein Q14524 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-253456 0.464 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f miannu YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-277639 0.7 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 25520508 t miannu We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG. SIGNOR-260750 0.307 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 0.7 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 0.8 RUNX1 protein Q01196 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR form complex binding 9606 BTO:0001271 10207087 t miannu We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function SIGNOR-66963 0.351 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 0.777 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 0.8 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser204 KLIDRTEsLNRSIEK -1 8995217 t miannu LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils SIGNOR-250147 0.637 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258908 0.8 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 0.666 CRH protein P06850 UNIPROT CRHR2 protein Q13324 UNIPROT up-regulates activity binding 9606 23504413 t lperfetto The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. |CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity SIGNOR-268611 0.917 CDC25B protein P30305 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates dephosphorylation 9606 7880537 t lperfetto Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex SIGNOR-217511 0.768 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser6 sPLLEVKG -1 24510915 t miannu Tryptic digests of KIFC1 treated with CDK1/CYCLIN B were analyzed by LC-MS/MS revealing phosphorylation at Ser6 (Supplementary Fig S5B). These data indicate that phosphorylation by CDK1/CYLCIN B contributes to KIFC1 stability by protecting KIFC1 from APC/C-mediated ubiquitination and subsequent proteasomal degradation. SIGNOR-266113 0.423 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 0.4 Vps34 Complex I complex SIGNOR-C242 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 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-260323 0.7 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 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-248755 0.738 ADAM17 protein P78536 UNIPROT GP1BA protein P07359 UNIPROT down-regulates activity cleavage Val466 ATSPTILvSATSLIT 9606 BTO:0000132 25297919 t lperfetto GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density SIGNOR-261861 0.284 CRP protein P02741 UNIPROT CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004910 26961257 f miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. SIGNOR-252143 0.477 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 0.8 SF3B4 protein Q15427 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-270666 0.768 DOT1L protein Q8TEK3 UNIPROT H3C1 protein P68431 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 t miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. SIGNOR-267141 0.2 KAT2A protein Q92830 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-269588 0.735 PRKCH protein P24723 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 t miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. SIGNOR-276049 0.2 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 0.269 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190696 0.8 SEC63 protein Q9UGP8 UNIPROT SEC62 protein Q99442 UNIPROT up-regulates activity binding 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265273 0.96 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 f miannu We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. SIGNOR-262502 0.2 ITGB1 protein P05556 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253180 0.82 NSFL1C protein Q9UNZ2 UNIPROT CTSL protein P07711 UNIPROT down-regulates activity binding -1 15498563 t lperfetto The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L. SIGNOR-265043 0.2 KLF6 protein Q99612 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 15917248 f fspada We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. SIGNOR-137807 0.7 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9330863 t gcesareni The eph family receptors and ligands. SIGNOR-51932 0.83 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser437 SGIVTNGsFSSSNAE 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249305 0.433 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 0.2 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 0.2 EEF1A1 protein P68104 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269511 0.8 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 0.2 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 0.418 SRC protein P12931 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276189 0.2 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 0.643 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 20444238 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-165212 0.422 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 0.471 GPR35 protein Q9HC97 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256860 0.2 MAGED1 protein Q9Y5V3 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887 20646279 f gcesareni These data demonstrate for the first time that maged1 is an important factor required for proper skeletal myoblast differentiation and muscle healing. SIGNOR-166896 0.7 ELOVL7 protein A1L3X0 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-267888 0.8 bosutinib chemical CHEBI:39112 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-258089 0.8 GNB3 protein P16520 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 14668344 t gcesareni Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein. SIGNOR-120264 0.4 BMS 794833 chemical CID:44155856 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190422 0.8 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 9261115 t To determine whether the COOH-terminal or other phosphotyrosine residues within Src are subject to dephosphorylation by SHP-1, the effects of this phosphatase on Src tyrosine phosphorylation were initially examined using CNBr cleavage analysis. As illustrated in Fig.1 A, CNBr treatment of 32P-labeled human Src has been shown previously to yield phosphorylated cleavage fragments of about 31, 9.7, and 4.7 kDa, which, respectively, contain the Src NH2-terminal region encompassing the major sites for serine phosphorylation on Src, Ser-12 and Ser-17 (31-kDa fragment), the inhibitory tyrosine phosphorylation site, Tyr-530 (4.7-kDa fragment), and a key site for autophosphorylation on activated Src, Tyr-419 [} These observations, together with the finding of reduced Src activity in HEY cells expressing a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation. SIGNOR-248473 0.527 naratriptan chemical CHEBI:7478 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258338 0.8 RFX complex complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 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-253990 0.286 PDXP protein Q96GD0 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity dephosphorylation Ser166 SSRRRAIsETEENSD 9606 33414453 t miannu Considering the roles of NF2 in actin dynamics and Mdm2 regulation  - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38. SIGNOR-277151 0.2 monoisononyl phthalate chemical CHEBI:132593 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-268778 0.8 DNA_damage stimulus SIGNOR-ST1 SIGNOR PALB2 protein Q86YC2 UNIPROT up-regulates activity 9606 BTO:0001938 19369211 f lperfetto Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations. SIGNOR-244490 0.7 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 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity chemical activation 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate SIGNOR-264129 0.8 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol. SIGNOR-251006 0.328 PDHX protein O00330 UNIPROT GCG protein P01275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001731 12783165 f miannu In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. SIGNOR-254901 0.2 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275981 0.536 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000567 9687510 t gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha SIGNOR-59447 0.615 CUDC-907 chemical CID:54575456 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191157 0.8 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 0.542 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 BTO:0000246 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248392 0.295 KAT2A protein Q92830 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 BTO:0000150 SIGNOR-C7 15009097 t gcesareni 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-123315 0.337 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -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-106514 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276592 0.388 clofarabine chemical CHEBI:681569 ChEBI POLG2 protein Q9UHN1 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258362 0.8 ZNF76 protein P36508 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-266221 0.347 carfilzomib chemical CHEBI:65347 ChEBI PSMB8 protein P28062 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000873 19348473 t Luana Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes. SIGNOR-257819 0.8 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32195003 f Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR SIGNOR-261534 0.2 RIMBP2 protein O15034 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264361 0.501 Oxotremorine chemical CHEBI:7851 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258653 0.8 Condensin I complex SIGNOR-C341 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-263907 0.7 EPAS1 protein Q99814 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271586 0.2 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser9 STRSVSSsSYRRMFG -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-248876 0.284 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 0.2 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser272 LSASPQPsSVAPRRP 10090 BTO:0002284 19833727 t We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose SIGNOR-255567 0.2 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 0.8 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 0.246 BMP7 protein P18075 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7644468 t acerquone In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7. SIGNOR-30512 0.804 CCNA2 protein P20248 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR form complex binding 9606 29870721 t lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. SIGNOR-267571 0.922 FYN protein P06241 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-247155 0.734 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser179 TASGSSVsPGLYSKT 9606 BTO:0000567 35469017 t miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. SIGNOR-276721 0.2 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser435 KKLERNLsFEIKKVP 9606 7520867 t llicata Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435. our results suggest that both pkc and pka are capable of phosphorylating, and therefore inhibiting, ptp-pest in vivo SIGNOR-27304 0.322 PF-03814735 chemical CID:49830590 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205950 0.8 PSTPIP1 protein O43586 UNIPROT ABL1 protein P00519 UNIPROT down-regulates 9606 11163214 f lperfetto Cytoskeletal protein pstpip1 directs the pest-type protein tyrosine phosphatase to the c-abl kinase to mediate abl dephosphorylationSeveral experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity SIGNOR-105035 0.597 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LCK protein P06239 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 8618896 t inferred from 70% family members lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. SIGNOR-270177 0.2 GSK3A protein P49840 UNIPROT IL17RA protein Q96F46 UNIPROT down-regulates quantity by destabilization phosphorylation Thr780 MVLTDPHtPYEEEQR 9606 BTO:0000007 26871944 t miannu Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.  SIGNOR-277206 0.2 PAX7 protein P23759 UNIPROT MLL1 complex complex SIGNOR-C89 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-217716 0.2 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 0.962 IKBKE protein Q14164 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser151 VLPSSKRsPSTATLS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276778 0.2 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-209647 0.87 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207087 0.8 TNF protein P01375 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 10485710 f lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-252733 0.317 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr307 IGPDNLPyVQILKTA 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-98630 0.2 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 0.683 COLGALT1 protein Q8NBJ5 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261155 0.402 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 0.8 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 0.377 CSNK1A1 protein P48729 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 11955435 t gcesareni In principle, pka, ck-1 and gsk3 can phosphorylate as many as 19 serine residues in gli3: fourpkasites, three primarygsk3sites, four primary ck-1 sites and eight secondary gsk3 and ck-1 sites SIGNOR-116512 0.6 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 0.2 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t miannu Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome SIGNOR-74708 0.441 CYP21A2 protein P08686 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI up-regulates quantity chemical modification 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-268645 0.8 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni Ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. SIGNOR-76096 0.304 ME1 protein P48163 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267055 0.8 YY1 protein P25490 UNIPROT TNFRSF10B protein O14763 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 34589486 t miannu Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis. SIGNOR-268793 0.403 CCND1 protein P24385 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-250680 0.951 MAPK14 protein Q16539 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR up-regulates phosphorylation 9606 21902831 t lperfetto P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling. SIGNOR-217676 0.372 MAPK14 protein Q16539 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates activity phosphorylation Thr735 KPFPAPQtPGRLQPA 10029 BTO:0000246 20188673 t gcesareni We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38alpha MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr(735), which is required for TACE-mediated ectodomain shedding SIGNOR-163970 0.405 MAPK1 protein P28482 UNIPROT SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation Thr622 LGTQVPGtPPPKYNT -1 11805112 t lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-249448 0.36 SDHAF2 protein Q9NX18 UNIPROT SDHB protein P21912 UNIPROT up-regulates binding 9606 19628817 t miannu Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity SIGNOR-187239 0.617 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 0.74 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 12244043 f azuccotti Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes SIGNOR-254989 0.7 NUMA1 protein Q14980 UNIPROT TUBD1 protein Q9UJT1 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-117159 0.2 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F10 protein P00742 UNIPROT up-regulates activity binding 9606 BTO:0000131 32665005 t lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. SIGNOR-263543 0.652 HNF1A protein P20823 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10050749 t lperfetto Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α SIGNOR-251720 0.301 NBEAL2 protein Q6ZNJ1 UNIPROT Platelet_morphogenesis phenotype SIGNOR-PH135 SIGNOR up-regulates 9606 BTO:0000132 28082341 f lperfetto We compared platelet size and number of α-granules for two NBEAL2 and two GATA1-deficient patients and found reduced numbers of α-granules for all, with the defect being more pronounced for NBEAL2 deficiency.  SIGNOR-261882 0.7 LRAT protein O95237 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 10090 18093970 t lperfetto We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis SIGNOR-265110 0.8 STMN3 protein Q9NZ72 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates quantity by destabilization binding 22577147 t lperfetto  Stathmins can thus sequester free tubulin that may result in inhibiting microtubule growth and/or promoting microtubule collapse SIGNOR-264896 0.7 SERPINC1 protein P01008 UNIPROT F12 protein P00748 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264139 0.6 CNTF protein P26441 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 10966616 t gcesareni Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr) SIGNOR-81382 0.742 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 0.33 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 0.36 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 23074268 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-199104 0.2 MAPK9 protein P45984 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Thr200 IARYVPStPWFLMPI 9606 15805466 t llicata Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation. SIGNOR-134878 0.472 MMP2 protein P08253 UNIPROT LAMC2 protein Q13753 UNIPROT up-regulates activity cleavage 9211848 t lperfetto Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling. SIGNOR-253240 0.471 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCB protein P05771 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-242584 0.8 STOX1 protein Q6ZVD7 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000601 22728895 t Gianni In this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A. SIGNOR-269065 0.2 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 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 26088133 t lperfetto Interestingly, GSK3beta can be released from the multienzyme complex in response to PKA phosphorylation on serine 9, which suppresses GSK3beta activity. SIGNOR-264819 0.2 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 0.78 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 0.397 NEU1 protein Q99519 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates activity 9606 BTO:0000182 19151752 f Giorgia In HT-29 cells cultured with 10% fetal bovine serum (FBS), the phosphorylation of integrin β4 was significantly decreased in NEU1-overexpressing cells and the level seemed to be inversely correlated with the sialidase activity. These results suggest that NEU1 is involved in the regulation of integrin β4 phosphorylation probably through desialylation in colon cancer cells. SIGNOR-260655 0.2 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 0.275 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 10090 17341133 t lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. SIGNOR-235388 0.654 SEC23IP protein Q9Y6Y8 UNIPROT SEC23B protein Q15437 UNIPROT up-regulates activity binding 10090 BTO:0000142 10400679 t lperfetto The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway. SIGNOR-265306 0.347 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 0.2 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275877 0.2 DGC complex SIGNOR-C217 SIGNOR NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265449 0.281 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 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-255788 0.691 SAGA complex complex SIGNOR-C465 SIGNOR H3-3A protein P84243 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-269629 0.2 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 0.582 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates activity binding 9031 BTO:0000140 12478285 t lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors. SIGNOR-219221 0.611 PRKCZ protein Q05513 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276017 0.2 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 0.401 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 0.638 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10037602 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-64964 0.858 AKT1 protein P31749 UNIPROT SCYL1 protein Q96KG9 UNIPROT up-regulates activity phosphorylation Thr469 STRHRVLtSAFSRAT 9606 BTO:0000567 24769208 t lperfetto In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions.|A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification. SIGNOR-265496 0.255 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr456 PPHLKYLyLVVSDSG 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-251351 0.812 PKA proteinfamily SIGNOR-PF17 SIGNOR 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-267408 0.2 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser541 KRTKASMsEFLESED 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-275555 0.362 SHH protein Q15465 UNIPROT GLI2 protein P10070 UNIPROT up-regulates activity 9606 BTO:0001593 16880529 f lperfetto Finally, Sonic hedgehog (Shh) stimulates BMP-2 promoter activity and osteoblast differentiation, and the effects of Shh are mediated by Gli2. SIGNOR-148349 0.729 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Thr263 PSRPPPPtPRRPASV 9606 BTO:0000007 16446428 t gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 SIGNOR-249579 0.654 USP24 protein Q9UPU5 UNIPROT DDB2 protein Q92466 UNIPROT up-regulates deubiquitination 9606 23159851 t miannu Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation SIGNOR-199731 0.703 CSNK2A1 protein P68400 UNIPROT TERF1 protein P54274 UNIPROT up-regulates phosphorylation Thr122 LTACQLRtIYICQFL 9606 18347021 t lperfetto Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. Mapping of the ck2 target site identified threonine 122 as a substrate in trf1. A threonine to alanine change at this position led to a diminished dna binding due to reduced dimerization of trf1. SIGNOR-178034 0.2 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr154 SSKRSPStATLSLPS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276777 0.643 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 0.2 Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR F10 protein P00742 UNIPROT up-regulates activity cleavage 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263538 0.571 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 0.309 SNRPD3 protein P62318 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270686 0.927 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 t miannu Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687 SIGNOR-168385 0.2 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 0.374 MITF protein O75030 UNIPROT TYRP1 protein P17643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 22371403 f miannu MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. SIGNOR-254591 0.487 KLF6 protein Q99612 UNIPROT DLK1 protein P80370 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15917248 f Repression of Dlk1 requires HDAC3 deacetylase activity fspada We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. SIGNOR-137836 0.282 ITCH protein Q96J02 UNIPROT TRPV4 protein Q9HBA0 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 17110928 t miannu AIP4 ubiquitin ligase is involved in the ubiquitination of both TRPV4 and TRPC4.Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. SIGNOR-272625 0.377 POLR3G protein O15318 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266127 0.698 LRIG1 protein Q96JA1 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates ubiquitination 9606 16123311 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-139951 0.434 PRMT1 protein Q99873 UNIPROT FUS protein P35637 UNIPROT down-regulates activity methylation 9606 BTO:0000567 30354839 t lperfetto PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis. SIGNOR-262274 0.485 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 9606 7791754 t fspada  BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor.  SIGNOR-232216 0.778 DBH protein P09172 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI up-regulates quantity chemical modification 10090 7961964 t brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. SIGNOR-264006 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 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-217181 0.729 H2BC11 protein P06899 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-263727 0.2 MYCN protein P04198 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000793;BTO:0002104 7923112 f miannu Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. SIGNOR-254616 0.369 LRRK2 protein Q5S007 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease SIGNOR-260267 0.33 ZNF322 protein Q6U7Q0 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24550733 t lperfetto Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription. SIGNOR-264900 0.2 CAMK2B protein Q13554 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 15980064 t gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. SIGNOR-138360 0.2 CHEK1 protein O14757 UNIPROT TLK1 protein Q9UKI8 UNIPROT down-regulates phosphorylation Ser743 PHMRRSNsSGNLHMA 9606 12660173 t llicata Chk1 phosphorylates tlk1 on serine 695 (s695) these findings identify an unprecedented functional co- operation between atm and chk1 in propagation of a checkpoint response during s phase and suggest that, through transient inhibition of tlk kinases, the atm_chk1_tlk pathway may regulate processes involved in chromatin assembly. SIGNOR-99653 0.431 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation 9606 23405013 t inferred from 70% family members lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling SIGNOR-270013 0.2 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 0.748 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16899510 t Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. SIGNOR-259849 0.299 SMC3 protein Q9UQE7 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 t miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. SIGNOR-264537 0.82 RPS6KA3 protein P51812 UNIPROT GSK3A protein P49840 UNIPROT down-regulates activity phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000130 11583116 t lperfetto P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively. SIGNOR-110827 0.265 LATS1 protein O95835 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-197643 0.791 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 0.731 oxymetazoline chemical CHEBI:7862 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9913 BTO:0000142 9632357 t miannu Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives. SIGNOR-258927 0.8 DOT1L protein Q8TEK3 UNIPROT 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-256143 0.4 RFX complex complex SIGNOR-C104 SIGNOR HLA-DOA protein P06340 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-253994 0.328 PLCB3 protein Q01970 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate(6-) smallmolecule CHEBI:203600 ChEBI up-regulates quantity chemical modification 9606 23994464 t apalma The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores SIGNOR-255018 0.8 DIO3 protein P55073 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-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-266941 0.8 PRKDC protein P78527 UNIPROT USF1 protein P22415 UNIPROT up-regulates phosphorylation 9606 19303849 t miannu Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation. SIGNOR-184849 0.293 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 0.745 CAMKK2 protein Q96RR4 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates phosphorylation Thr483 KHIPSLAtVILVKTM 9606 22778263 t lperfetto It has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of thr-482, a post-translational change that likely contributes to the increased autonomous activity of camkk2 SIGNOR-198107 0.2 CTSE protein P14091 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Phe834 QLEASPAfLAVPVEK -1 12631277 t lperfetto Disruption of structural and functional integrity of alpha 2-macroglobulin by cathepsin E|Analysis of the N-terminal amino-acid sequences of these proteins revealed that alpha 2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region. SIGNOR-266977 0.38 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 0.2 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 0.479 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates activity chemical inhibition -1 20565110 t We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling. SIGNOR-259995 0.8 SIRT1 protein Q96EB6 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20089851 f Regulation miannu SIRT1 deacetylates and activates the FOXOs under oxidative stress, thereby inducing Mn-SOD expression SIGNOR-251763 0.491 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3B complex SIGNOR-C43 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-90839 0.79 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Thr306 LKGAILTtMLATRNF 9606 1324926 t lperfetto After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314 SIGNOR-17316 0.2 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates phosphorylation Tyr619 NKVDDCNyAIKRIRL 9606 17998206 t lperfetto We show that perk is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of perk, is essential for autocatalytic activity. SIGNOR-159156 0.2 CCR1 protein P32246 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255118 0.311 PSAT1 protein Q9Y617 UNIPROT O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI up-regulates activity chemical modification 3702 30034403 t lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. SIGNOR-268560 0.8 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser83 NKEKKAVsPLLLTTT 9606 11152499 t tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. SIGNOR-85769 0.2 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT down-regulates activity sumoylation Lys350 PPIPRAVkPEPTNSS 9606 BTO:0000007 14701874 t gianni We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1. SIGNOR-269112 0.583 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 0.563 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser249 DTRQIQPsPPWSYDQ 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-138969 0.2 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 0.405 Niflumic acid chemical CHEBI:34888 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-258062 0.8 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 0.2 FLT3 protein P36888 UNIPROT CISH protein Q9NSE2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 f The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD SIGNOR-261542 0.299 DRD2 protein P14416 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-256844 0.557 ZNF76 protein P36508 UNIPROT TBP protein P20226 UNIPROT down-regulates activity binding 9606 15280358 t miannu We identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression. SIGNOR-224650 0.399 MRPS34 protein P82930 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-261443 0.667 SHANK2 protein Q9UPX8 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-264606 0.7 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 0.2 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 0.43 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A SIGNOR-260833 0.843 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 0.8 FANCD2 protein Q9BXW9 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263255 0.745 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 0.966 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 0.8 MSX1 protein P28360 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001103 15192231 f gcesareni We found that msx1 and h1b bind to a key regulatory element of myod, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin. SIGNOR-125765 0.425 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 0.843 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-230733 0.422 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser465 VRRDRSTsIKLQEAP 9606 19261611 t llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. SIGNOR-184460 0.2 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 0.294 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 0.8 CDC25A protein P30304 UNIPROT CDK4 protein P11802 UNIPROT up-regulates activity dephosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 27485204 t miannu Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14 and Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14 and Y15)-cyclin A/B    .|Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14/Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14/Y15)-cyclin A/B . SIGNOR-277138 0.705 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 0.831 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148595 0.385 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 0.2 MAPKAPK5 protein Q8IW41 UNIPROT MAPK4 protein P31152 UNIPROT up-regulates phosphorylation Ser186 YSHKGYLsEGLVTKW 9606 1319925 t lperfetto This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex. SIGNOR-17069 0.63 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 0.777 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 0.956 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Thr305 KLKGAILtTMLATRN 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-17312 0.2 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165043 0.513 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 0.8 GATA1 protein P15976 UNIPROT SPTA1 protein P02549 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10037687 f Regulation of expression miannu GATA-1 and CACCC-related Proteins Are Both Major Activators of the Human Erythroid β-Spectrin Gene Promoter SIGNOR-251928 0.377 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity acetylation 9606 22298955 t gcesareni Bmp-induced non-smad erk signaling pathway cooperatively regulates osteoblast differentiation, in part, through increasing the stability and transcriptional activity of runx2 or increasing runx2 acetylation by p300. SIGNOR-195579 0.453 HTR2C protein P28335 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-257295 0.435 ECM stimulus SIGNOR-ST20 SIGNOR Av/b2 integrin complex SIGNOR-C176 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-259054 0.7 HTR1A protein P08908 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-256693 0.494 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 0.316 MITF protein O75030 UNIPROT DCT protein P40126 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22371403 f miannu MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. SIGNOR-254592 0.461 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249643 0.708 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser60 RLPGRSTsLVEGRSC -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-250155 0.699 RPL31 protein P62899 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-262469 0.865 ACVR1B protein P36896 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 14517293 t gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway SIGNOR-235160 0.741 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 0.459 SOX17 protein Q9H6I2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity 10090 33083751 f SimoneGraziosi Sox17 prevents beta-catenin activation by increasing its phosphorylation, particularly in WM lesions SIGNOR-269268 0.686 TTK protein P33981 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15618221 t lperfetto Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage SIGNOR-132665 0.292 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 0.395 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 0.2 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 0.321 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 0.773 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 0.896 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t gcesareni These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor. SIGNOR-252555 0.654 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 0.401 IRS1 protein P35568 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10116 BTO:0001103 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-175668 0.813 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity binding 9534 BTO:0004055 11278538 t lperfetto 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-219301 0.867 ELP3 protein Q9H9T3 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-269710 0.807 NEK6 protein Q9HC98 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser608 VLKNLNNsNLFSPVN -1 21335236 t done miannu To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization SIGNOR-273892 0.315 RUNX2 protein Q13950 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20740684 t Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1-IC-RBP-Jk complex gcesareni Runx2 is an inhibitor of the notch1 signaling pathway during normal osteoblast differentiation. The n-terminal domain of runx2 was crucial to the binding and inhibition of the the n-terminus of the notch1 intracellular domain. SIGNOR-167627 0.38 WNT9A protein O14904 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. SIGNOR-195972 0.2 RBCK1 protein Q9BYM8 UNIPROT BACH1 protein O14867 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 17682061 t miannu HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process. SIGNOR-236971 0.345 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr252 EAYPEEAyIADLDAK 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-274109 0.265 Av/b8 integrin complex SIGNOR-C185 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-257730 0.585 CSNK2A1 protein P68400 UNIPROT NOL3 protein O60936 UNIPROT up-regulates activity phosphorylation Thr149 SEAVQSGtPEEPEPE 9606 BTO:0000007 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-262837 0.324 PAS complex complex SIGNOR-C190 SIGNOR 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-) smallmolecule CHEBI:85342 ChEBI up-regulates quantity chemical modification -1 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. we demonstrate a central function for each component of the core protein machinery for PtdIns(3,5)P2 synthesis and turnover in the formation/detachment (or maturation) of transport vesicle intermediates from early endosomes. SIGNOR-253531 0.8 MLH1 protein P40692 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-71771 0.759 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 0.8 GNAQ protein P50148 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 BTO:0000944 12024019 t Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. SIGNOR-256520 0.419 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 0.283 IL4R protein P24394 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2. SIGNOR-100771 0.592 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 0.261 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 0.746 MAPK8 protein P45983 UNIPROT STAT6 protein P42226 UNIPROT down-regulates phosphorylation Ser707 IPPYQGLsPEESVNV 9606 21123173 t llicata Deactivation of stat6 through serine 707 phosphorylation by jnk. SIGNOR-170153 0.353 HCRTR2 protein O43614 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-257124 0.25 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 0.304 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 0.2 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by stabilization phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 t Manara Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. SIGNOR-260905 0.37 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 18574241 t lperfetto Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity SIGNOR-216888 0.353 TFE3 protein P19532 UNIPROT CTSA protein P10619 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276815 0.2 PFDN6 protein O15212 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270930 0.943 SHH protein Q15465 UNIPROT PTCH2 protein Q9Y6C5 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-217776 0.803 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 18758450 t lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-236119 0.428 FGD5 protein Q6ZNL6 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-260555 0.2 GCG protein P01275 UNIPROT GLP1R protein P43220 UNIPROT up-regulates binding 9606 BTO:0000776 7937318 t gcesareni In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin SIGNOR-34855 0.782 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 0.793 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 0.8 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 0.2 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 0.8 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 12421349 t The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax SIGNOR-95487 0.267 NFIX protein Q14938 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-268905 0.2 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 0.56 HNF1B protein P35680 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity binding 9606 BTO:0000007 9671480 t 2 miannu The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays. SIGNOR-241320 0.307 HSP90AA1 protein P07900 UNIPROT PAFAH1B1 protein P43034 UNIPROT up-regulates quantity by stabilization binding 9606 20133715 t miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability. SIGNOR-252168 0.522 DPYD protein Q12882 UNIPROT uracil smallmolecule CHEBI:17568 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-253988 0.8 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 0.514 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 0.7 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -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-33197 0.686 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1152 SERLKRTsQKVDLAL 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-132247 0.2 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 0.814 PTPRJ protein Q12913 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity dephosphorylation 9606 21262971 t miannu Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation. SIGNOR-277092 0.49 TGFBR1 protein P36897 UNIPROT RHOA protein P61586 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-227499 0.64 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 0.2 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr386 IGLNQPStPTHAAGV 9606 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-236498 0.75 CDK5 protein Q00535 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser400 IHKVILGsPAHRAGL 9606 21701498 t lperfetto Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress SIGNOR-174598 0.456 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75025 0.791 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 0.8 PIK3CG protein P48736 UNIPROT TPM2 protein P07951 UNIPROT up-regulates activity phosphorylation Ser61 EDEVEKYsESVKEAQ -1 16094730 t miannu Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. SIGNOR-263028 0.335 CSNK2A1 protein P68400 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser358 AKVLASLsDDEDEEE 9606 16428860 t lperfetto Phosphorylation of rangap1 stabilizes its interaction with ran and ranbp1. Serine-358 (358s) was identified as the major phosphorylation site. Experiments using purified recombinant kinase and specific inhibitors such as drb and apigenin strongly suggest that casein kinase ii (ck2) is the responsible kinase SIGNOR-143948 0.31 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 0.939 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 15952796 t inferred from 70% family members 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-270178 0.2 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 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-257464 0.8 CSNK1E protein P49674 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 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-230747 0.366 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 0.2 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr154 QLNDSAAyYLNDLDR -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277227 0.464 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-255970 0.2 SF3A3 protein Q12874 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 t miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263949 0.974 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248632 0.748 DOK1 protein Q99704 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257685 0.297 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser358 ELRKTQTsMSLGTTR -1 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266439 0.753 C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg751 HKDMQLGrLHMKTLL 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263482 0.558 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 0.428 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC3R protein P41968 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257537 0.8 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 0.2 STX16 protein O14662 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-253079 0.805 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 0.8 ARHGAP40 protein Q5TG30 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260497 0.41 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-38029 0.595 TPH2 protein Q8IWU9 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264012 0.8 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 0.446 PTPRZ1 protein P23471 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity dephosphorylation Tyr1105 RNEEENIySVPHDST 10090 BTO:0000601 16513268 t Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo. SIGNOR-248451 0.417 FLT3 protein P36888 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 f Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. SIGNOR-261519 0.42 PPARGC1A protein Q9UBK2 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-255060 0.395 GRPR protein P30550 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-257247 0.268 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 0.298 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 0.296 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-145288 0.2 AKT2 protein P31751 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 t llicata Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression SIGNOR-130260 0.375 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 0.2 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 0.727 RPS6KB1 protein P23443 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 7838153 t gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. SIGNOR-34117 0.595 PRKCA protein P17252 UNIPROT PTGIR protein P43119 UNIPROT unknown phosphorylation Ser328 TPLSQLAsGRRDPRA 9606 BTO:0000007 9722557 t lperfetto These results indicate that PKC-dependent phosphorylation is of critical importance to homologous regulation of hIP. Ser-328 is a primary site for PKC phosphorylation of hIP. SIGNOR-249011 0.323 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. replacement of Ser383 to Gly (S383G) reduced but still retained nearly half of the kinase activity of the wild-type. SIGNOR-250293 0.834 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr250 PFLLDEDyEKVLGYV BTO:0000007 12540842 t lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2. SIGNOR-249371 0.343 CHFR protein Q96EP1 UNIPROT PBK protein Q96KB5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24012691 t miannu CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a). SIGNOR-271471 0.346 Caspase 3 complex complex SIGNOR-C221 SIGNOR DFFA protein O00273 UNIPROT up-regulates activity cleavage 9606 9108473 t lperfetto DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3. SIGNOR-256464 0.755 PTK6 protein Q13882 UNIPROT CBL protein P22681 UNIPROT down-regulates activity phosphorylation 9606 23352614 t miannu Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl. SIGNOR-279348 0.488 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 11416147 t gcesareni One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks SIGNOR-108577 0.376 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT down-regulates transcriptional regulation 9606 18391014 f fspada We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice. SIGNOR-210117 0.3 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 0.411 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 0.601 ZBTB20 protein Q9HC78 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23776228 t miannu ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription. SIGNOR-266868 0.259 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 0.633 GATA3 protein P23771 UNIPROT CEBPB protein P17676 UNIPROT down-regulates binding 10090 15632071 t fspada In the present study, we demonstrate that both gata-2 and gata-3 form protein complexes with ccaat/enhancer binding protein alpha (c/ebpalpha) and c/ebpbeta, members of a family of transcription factors that are integral to adipogenesis. []the interaction between gata and c/ebp factors is critical for the ability of gata to suppress adipocyte differentiation. SIGNOR-132952 0.352 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr219 SIQGHNDyMCPATNQ 9606 BTO:0000150 20101225 t gcesareni Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes. SIGNOR-163562 0.446 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 0.8 adapalene chemical CHEBI:31174 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9606 BTO:0000404 30836068 t miannu Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβindermalfibroblasts (Kd value 34 nM) and RARγin the epidermis (Kdvalue 130 nM) SIGNOR-258487 0.8 LPCAT1 protein Q8NF37 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272760 0.8 SAGA complex complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269635 0.2 MAP3K7 protein O43318 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation 10094049 t lperfetto The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway. SIGNOR-262833 0.564 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRM1 protein P35372 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-257554 0.8 SEMA3B protein Q13214 UNIPROT NRP1 protein O14786 UNIPROT up-regulates activity binding 9606 25335892 t miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. SIGNOR-261814 0.753 GDF6 protein Q6KF10 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 16049014 t lperfetto We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins. SIGNOR-217526 0.6 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 0.748 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 0.271 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 18448069 t lperfetto Here, we report that AIMP1 negatively regulates TGF-_ signaling via stabilization of Smurf2. SIGNOR-227470 0.391 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 0.2 Substance P smallmolecule CHEBI:80308 ChEBI TACR1 protein P25103 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-257586 0.8 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 8355 BTO:0000964 8700149 t inferred from family member miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. SIGNOR-267794 0.8 PRKAA1 protein Q13131 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 SIGNOR-C15 12065600 t llicata Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro. SIGNOR-89760 0.399 afimoxifene chemical CHEBI:44616 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-258595 0.8 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174836 0.29 KDM6A protein O15550 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys28 LATKAARkSAPATGG 9606 24561908 t This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. SIGNOR-260017 0.2 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 0.295 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 0.34 PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity 9606 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-209856 0.732 ZWINT protein O95229 UNIPROT KNL1 complex complex SIGNOR-C363 SIGNOR form complex binding 27881301 t lperfetto KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits. SIGNOR-265194 0.2 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 0.2 DTX1 protein Q86Y01 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 11564735 t gcesareni We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300. SIGNOR-110629 0.381 MC2R protein Q01718 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268694 0.516 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 0.8 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERP44 protein Q9BS26 UNIPROT up-regulates 9606 11847130 f miannu Like many ER folding factors, ERp44 transcripts are induced by agents that cause the accumulation of unfolded proteins in the ER. SIGNOR-261047 0.7 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 0.498 C1S protein P09871 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-263394 0.707 PRKCH protein P24723 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by stabilization 9606 28939105 f miannu The results of our present study show that PKCη positively regulates the anti-apoptotic Bcl-2 family protein Mcl-1 by preventing its degradation via the proteasomal pathway involving Mcl-1 ubiquitin ligase Mule. SIGNOR-261908 0.2 MCF2 protein P10911 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260556 0.754 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 f IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254502 0.509 PDPK2P protein Q6A1A2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 15505410 t gcesareni Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2. SIGNOR-129965 0.2 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser381 GYSFVAPsILFKRNA 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131395 0.2 TUBGCP3 protein Q96CW5 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 t lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” SIGNOR-262327 0.782 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1044 YPFVRTGsPRRIQLS 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. site-directed mutagenesis of s1044 to an alanine resulted in the specific loss of d5 when this mutant was ectopically expressed in t98g cells and labelled by [32p]orthophosphate (figure 4b), proving that phosphorylation of s1044 gave rise to the tryptic phosphopeptide d5: tgspr. SIGNOR-104660 0.849 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 0.32 PLK1 protein P53350 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates phosphorylation Ser177 SSGSSEDsFVEIRMA 9606 22365832 t lperfetto Here we show that at mitotic entry, plk1 phosphorylates optineurin (optn) at serine 177 and that this dissociates optn from the golgi-localized gtpase rab8, inducing its translocation into the nucleus. SIGNOR-196367 0.539 EGLN3 protein Q9H6Z9 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates quantity by stabilization hydroxylation Pro395 VGHQGTVpSDNIDSQ 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-262007 0.318 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Ser6 sLHDALSG 9606 BTO:0000150 15121858 t llicata These results indicate that phosphorylation of gal-3 promotes its nuclear export after apoptotic stimuli through enhanced nuclear export. SIGNOR-124583 0.308 SP3 protein Q02447 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-253665 0.2 PRKCA protein P17252 UNIPROT 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-275672 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 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-254509 0.581 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation 9606 16751101 t lperfetto Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. SIGNOR-217628 0.668 EGFR protein P00533 UNIPROT NCK2 protein O43639 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-64731 0.399 FAM8A1 protein Q9UBU6 UNIPROT SYVN1 protein Q86TM6 UNIPROT up-regulates activity binding 9606 BTO:0000007 28827405 t miannu FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp SIGNOR-261348 0.577 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -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-248875 0.489 SB 505124 chemical CHEBI:100922 ChEBI ACVR1B protein P36896 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206736 0.8 CDC14B protein O60729 UNIPROT USP9X protein Q93008 UNIPROT down-regulates quantity by destabilization dephosphorylation 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-275613 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser174 LESSPTAsGSSVSPG 9606 BTO:0000567 35469017 t miannu CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2). SIGNOR-276719 0.2 UNC5 proteinfamily SIGNOR-PF98 SIGNOR DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268168 0.2 BLOC-1 complex SIGNOR-C381 SIGNOR serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity relocalization 9606 23805129 t lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules SIGNOR-265999 0.8 CDK5 protein Q00535 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr212 VIEPLPVtPTRDVAT 9534 BTO:0004055 11604394 t lperfetto Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase. SIGNOR-249328 0.54 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr680 IEDSREAtHSSGFSG 9606 23079597 t lperfetto Phosphorylation of kard by plk1 promotes direct interaction of bubr1 with the pp2a-b56_ phosphatase that counters excessive aurora b activity at kinetochores. We propose that plk1 and bubr1 cooperate to stabilize kinetochore-microtubule interactions. Phosphorylation of t680 by plk1 is essential for kard function SIGNOR-199222 0.84 CSNK1D protein P48730 UNIPROT TOP2B protein Q02880 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1132 QNQHDDSsSDSGTPS 9606 32015321 t miannu Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.CK1 binds with and phosphorylates TOP2β at Ser1130 to promote its degradation by VM-26. SIGNOR-277509 0.2 GSK3B protein P49841 UNIPROT BCL2L12 protein Q9HB09 UNIPROT up-regulates phosphorylation Ser156 SESPRPCsLPIRPCY 9606 BTO:0000527 22262180 t lperfetto Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a) SIGNOR-195512 0.338 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 0.835 NR1I3 protein Q14994 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. SIGNOR-254438 0.445 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates activity dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t Coronin 1B inhibits filament nucleation by Arp2/3 complex and this inhibition is attenuated by phosphorylation of Coronin 1B at Serine 2, a site targeted by SSH1L. Coronin 1B also directs SSH1L to lamellipodia where SSH1L likely regulates Cofilin activity via dephosphorylation SIGNOR-248763 0.446 MRAP2 protein Q96G30 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252367 0.505 TLN1 protein Q9Y490 UNIPROT A10/b1 integrin complex SIGNOR-C167 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-257616 0.588 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 0.592 MMP13 protein P45452 UNIPROT FGB protein P02675 UNIPROT down-regulates quantity by destabilization cleavage Arg124 LQQERPIrNSVDELN -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain SIGNOR-263615 0.2 KAT2B protein Q92831 UNIPROT H3Y1 protein P0DPK2 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-269614 0.2 KASH5 protein Q8N6L0 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-263290 0.2 MAPK8 protein P45983 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-32421 0.78 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 0.603 CAMK2A protein Q9UQM7 UNIPROT HOMER proteinfamily SIGNOR-PF59 SIGNOR down-regulates activity phosphorylation -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-264699 0.395 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 0.2 a7/b1 integrin complex SIGNOR-C126 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-269007 0.7 MYF5 protein P13349 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 8382796 t lperfetto Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression SIGNOR-241494 0.241 LATS2 protein Q9NRM7 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity phosphorylation Thr178 VYHYRINtASDGKLY -1 23852372 t miannu  Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl.  Lats2 phosphorylates c-Abl at Thr197 in vitro. SIGNOR-276497 0.362 MAP3K6 protein O95382 UNIPROT MAP3K6 protein O95382 UNIPROT up-regulates activity phosphorylation Thr806 GITPCTEtFTGTLQY 9606 17210579 t Manara These results suggested that the induction of ASK2 phosphorylation in the presence of ASK1 is the consequence of autophosphorylation of ASK2. ASK1 thus appears to not only support the effective protein expression but also confer the kinase activity to ASK2. SIGNOR-260774 0.2 SRC protein P12931 UNIPROT ARHGAP5 protein Q13017 UNIPROT up-regulates activity phosphorylation Tyr1109 KGYSDEIyVVPDDSQ -1 9819392 t miannu Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Phosphorylation of Y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-Src than by the EGF receptor and was efficiently catalyzed by c-Src in vitro, indicating that Y1105 is a selective and preferential target of c-Src both in vitro and in vivo. SIGNOR-276170 0.607 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Ser14 TRVFKKSsPNCKLTV 10090 BTO:0002572 26324936 t done miannu ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration. SIGNOR-274018 0.2 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 0.654 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser122 NIIHGSDsVESAEKE -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-250301 0.2 NFIL3 protein Q16649 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto NFIL3 inhibits apoptosis without affecting Bcl-xL expression. SIGNOR-256618 0.7 FILIP1L protein Q4L180 UNIPROT FLNC protein Q14315 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000165 32444788 t miannu We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. SIGNOR-262618 0.252 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 0.8 DOCK3 protein Q8IZD9 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260548 0.656 tadalafil chemical CHEBI:71940 ChEBI PDE11A protein Q9HCR9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000815 21189023 t Luana All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11 SIGNOR-257888 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2K protein P61086 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271367 0.758 VCP protein P55072 UNIPROT AURKA protein O14965 UNIPROT down-regulates activity binding 6239 23649807 t lperfetto The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts SIGNOR-265044 0.313 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 0.8 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 0.7 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 0.638 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 0.666 GNGT1 protein P63211 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 12507995 t gcesareni Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma. SIGNOR-96831 0.487 TFIIH complex SIGNOR-C457 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t lperfetto Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7. SIGNOR-269356 0.306 RAB21 protein Q9UL25 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-260620 0.419 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr293 HRIDGKTyVIKRVKY -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-260784 0.2 tubastatin A chemical CHEBI:94186 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207450 0.8 TSC1 protein Q92574 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity binding 9606 20006481 t lperfetto Tsc1 and tsc2 proteins, which together inhibit rheb through the gap activity of tsc2. SIGNOR-162096 0.911 PLEKHG6 protein Q3KR16 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-260568 0.297 TWIST1 protein Q15672 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-255532 0.2 BTF3 protein P20290 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253948 0.251 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 0.2 GRN protein P28799 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates binding 9606 21393509 t gcesareni Collectively, these findings demonstrate that pgrn is a ligand of tnfr, an antagonist of tnf signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. SIGNOR-172684 0.492 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI HNF4G protein Q14541 UNIPROT down-regulates quantity by repression 9606 9792724 f miannu Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment. SIGNOR-254444 0.8 RARB protein P10826 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-133234 0.416 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 25056917 t P38α promotes multi‐site GATA‐2 phosphorylation, increasing its localization in nuclear foci enriched in an active form of RNA polymerase II and its capacity to regulate endogenous target genes. SIGNOR-259946 0.269 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 0.27 CHEK2 protein O96017 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr182 SHFVRVStAQKSKKG 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. SIGNOR-276908 0.526 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 0.532 SCF-SKP2 complex SIGNOR-C136 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 20852628 t gcesareni The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain SIGNOR-243551 0.568 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT 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-252614 0.893 APOE protein P02649 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe) SIGNOR-106221 0.635 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 0.381 F2R protein P25116 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257293 0.439 NLGN2 protein Q8NFZ4 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-264156 0.829 MAPK1 protein P28482 UNIPROT PFAS protein O15067 UNIPROT up-regulates phosphorylation Thr619 GQGDAPPtPLPTPVD 9606 32485148 t miannu T619 in PFAS is required to mediate ERK2-dependent purine synthesis stimulation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation. SIGNOR-267306 0.2 LHX4 protein Q969G2 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates quantity by expression transcriptional regulation 10029 BTO:0000246 15998782 t Luana We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. SIGNOR-266056 0.514 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 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270384 0.8 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 0.675 STAT6 protein P42226 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22025054 f lperfetto IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1). SIGNOR-249541 0.7 GPR132 protein Q9UNW8 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-257187 0.2 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263780 0.7 TLR2 protein O60603 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266746 0.608 TFEB protein P19484 UNIPROT NDUFA13 protein Q9P0J0 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276701 0.2 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates activity phosphorylation Tyr411 RVIEDNEyTAREGAK 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-251266 0.2 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t lperfetto Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. SIGNOR-106833 0.359 PPM1B protein O75688 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation -1 11104763 t miannu In vitro, PP2Cbeta-1 dephosphorylated and inactivated TAK1. SIGNOR-277154 0.551 FGG protein P02679 UNIPROT FN1 protein P02751 UNIPROT down-regulates activity binding 9606 2243140 t Regulation miannu Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a). SIGNOR-251970 0.553 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 0.2 ITGB1BP1 protein O14713 UNIPROT ITGB3 protein P05106 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-257656 0.308 FLT1 protein P17948 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-260060 0.261 furtrethonium chemical CHEBI:134764 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258643 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D4 protein Q9Y2X8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271341 0.737 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1062 AVKTVNEsASLRERI -1 7926007 t lperfetto Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites. SIGNOR-248905 0.348 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 0.7 PSME3 protein P61289 UNIPROT SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization binding 27511885 t lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. SIGNOR-275866 0.2 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser90 QHVRSHSsPASLQLG 9606 BTO:0000567 26183396 t miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. SIGNOR-276926 0.258 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 0.693 sulpiride chemical CHEBI:32168 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). SIGNOR-258430 0.8 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR unknown phosphorylation 9606 16046471 t lperfetto Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .we now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. .Ikkbeta Plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. . SIGNOR-217427 0.869 PRKCA protein P17252 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates phosphorylation Ser104 TKLTRIPsAKKYKDI 9606 BTO:0000149 15917297 t miannu Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect. SIGNOR-137841 0.384 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 0.7 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 22683405 t Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage gcesareni Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity. SIGNOR-197744 0.806 PI3K complex SIGNOR-C156 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000830 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-254951 0.278 NR1D2 protein Q14995 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 t miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. SIGNOR-268006 0.467 SKIL protein P12757 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253302 0.843 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by repression 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. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1. SIGNOR-188881 0.356 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 0.2 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 0.2 Upf-EJC complex SIGNOR-C367 SIGNOR Nonsense-mediated mRNA decay phenotype SIGNOR-PH175 SIGNOR up-regulates 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. the hUpf complex communicates with the EJC and triggers NMD in the cytoplasm. SIGNOR-265239 0.7 CDKN1A protein P38936 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni P21 and p27 are key inhibitors of both cdk1 and cdk2. SIGNOR-128442 0.881 PKA proteinfamily SIGNOR-PF17 SIGNOR TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 31057087 t inferred from 70% family members miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-270130 0.2 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252862 0.911 UCHL3 protein P15374 UNIPROT UBA52 protein P62987 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-270827 0.801 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 0.7 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 0.2 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248529 0.399 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-236018 0.556 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 9889196 t lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. SIGNOR-217328 0.942 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 0.319 EIF2S1 protein P05198 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24714526 f miannu Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy. SIGNOR-251818 0.2 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248967 0.439 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 0.2 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser396 TFDSLPSsPSSATPH -1 11500363 t miannu eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A] SIGNOR-250089 0.578 GTF2I protein P78347 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0000007 12493763 t lperfetto We identify a new family of HDAC1,2-associated complexes containing BHC110. Moreover, we define the polypeptide composition of a novel member of this family containing the candidate gene for X-linked mental retardation XFIM and the initiator-binding protein TFII-I. SIGNOR-268539 0.405 MYC protein P01106 UNIPROT PPAT protein Q06203 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-267381 0.2 NFX1 protein Q12986 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 9606 BTO:0004117 18505829 t miannu we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression. SIGNOR-226360 0.373 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 0.791 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 0.8 CSNK2A1 protein P68400 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-250832 0.371 EIF2AK1 protein Q9BQI3 UNIPROT HBB protein P68871 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-251780 0.2 GABRA6 protein Q16445 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-263768 0.536 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Thr107 PKKERRRtESINSAF 9606 BTO:0000007 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-249244 0.288 PTPN11 protein Q06124 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR down-regulates activity dephosphorylation 9606 16767162 t miannu Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals. SIGNOR-265824 0.435 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser356 DIKSNNWsLEDVTAS 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-140998 0.2 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation Tyr8 MASGDTLyIATDGSE 9606 BTO:0002181 26198631 t miannu In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B). SIGNOR-276930 0.2 BCR-Dk complex SIGNOR-C435 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-268441 0.715 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. SIGNOR-83732 0.582 ERO1B protein Q86YB8 UNIPROT ERP44 protein Q9BS26 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 11847130 t Simone Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits. SIGNOR-261048 0.2 L3MBTL2 protein Q969R5 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates quantity binding 9606 31225475 t miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266788 0.246 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 10339564 t lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. SIGNOR-217276 0.942 BMPR1A protein P36894 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-255261 0.688 PRKCA protein P17252 UNIPROT TACSTD2 protein P09758 UNIPROT down-regulates activity phosphorylation Ser322 GELRKEPsL 9606 BTO:0001109 31177095 t done miannu  Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation. SIGNOR-273821 0.2 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 0.355 RBM7 protein Q9Y580 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 30824372 t miannu Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). these findings establish that RBM7 binds 7SK snRNP and that genotoxic stress activates P-TEFb by relocating it from 7SK snRNP to the CTD of Pol II. SIGNOR-261182 0.2 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265436 0.2 TNIK protein Q9UKE5 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 t miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  SIGNOR-276334 0.2 FLT1 protein P17948 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276190 0.2 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 0.27 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 0.754 AKAP9 protein Q99996 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates activity binding 9606 BTO:0000182;BTO:0000666 27039663 t Giulio Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C). SIGNOR-260303 0.512 TFEB protein P19484 UNIPROT NDUFS4 protein O43181 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276705 0.246 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 0.301 AKT1 protein P31749 UNIPROT COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 t llicata Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6. SIGNOR-252532 0.282 ITGAL protein P20701 UNIPROT AKAP9 protein Q99996 UNIPROT up-regulates activity binding 9606 BTO:0001945 16339516 t Giulio However, association of CG-NAP/AKAP450 was signifi-cantly enhanced at 37°C in LFA-1-activated cells triggered toundergo motility. Taken together, our findings provide the first definitiveevidence that the protein CG-NAP/AKAP450 is a key scaffoldingcomponent of the multimolecular complex assembled in T cellsupon LFA cross-linking and is functionally indispensable for cellpolarity and migration induced by this integrin. SIGNOR-260304 0.2 BMPR2 protein Q13873 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 t lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-33443 0.628 CDC42BPB protein Q9Y5S2 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 10947843 t Manara In this study, we have shown that MRCKb phosphorylated moesin at Thr-558 | We have shown that the phosphorylation is important to the formation of ®lopodia, and that MRCK may regulate this formation through the phosphorylation of ERM proteins at the tip of ®lopodia. SIGNOR-260802 0.2 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC5R protein P33032 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-257539 0.8 EIF1 protein P41567 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity relocalization 9606 20921384 t lperfetto Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning SIGNOR-269143 0.527 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 0.2 FGF2 protein P09038 UNIPROT Gbeta proteinfamily SIGNOR-PF4 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-269908 0.2 ERG protein P11308 UNIPROT WNT3A protein P56704 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 23913826 t Luana Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression. SIGNOR-261598 0.2 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr842 CTETFTGtLQYMAPE 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-158431 0.2 NMDA receptor_2A complex SIGNOR-C347 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266599 0.281 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 0.396 MLXIPL protein Q9NP71 UNIPROT FAS protein P25445 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 15496471 t Luana The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) SIGNOR-267947 0.2 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 0.7 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 0.416 panobinostat chemical CHEBI:85990 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257752 0.8 RARG protein P13631 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t inferred from family member lperfetto We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-270296 0.419 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273106 0.755 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 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-174593 0.8 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 0.435 clozapine chemical CHEBI:3766 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-258513 0.8 HOXA13 protein P31271 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000942 21829694 t Luana Analysis of normalized luciferase expression confirmed that wt HOXA13 regulates gene expression through the EphA7 cis-regulatory DNA element SIGNOR-261631 0.291 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 0.7 HNF4A protein P41235 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867220 f miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. SIGNOR-255198 0.301 P2RY12 protein Q9H244 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-256991 0.2 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 16314496 t fstefani We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription. SIGNOR-142462 0.354 PRKCD protein Q05655 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr46 PHRYRPGtVALREIR 9606 19363025 t gcesareni We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation. SIGNOR-185144 0.2 SHC1 protein P29353 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-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-236363 0.77 CDC14B protein O60729 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity dephosphorylation 9606 18662541 t lperfetto Cdc14B activates APC/C Cdh1 after DNA damage in G2.|Importantly, after DNA damage, thein vivo phosphorylation of wild type Cdh1 - but not that of Cdh1 (4xA) - increased after Cdc14B silencing (XREF_FIG), indicating that in response to genotoxic stress, Cdc14B dephosphorylates Cdh1 on the four sites phosphorylated by Cdk2. SIGNOR-277017 0.313 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004408 29606353 t Gianni Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. SIGNOR-269067 0.446 MKRN1 protein Q9UHC7 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 23104211 t miannu Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation.The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. SIGNOR-272036 0.366 AKT proteinfamily SIGNOR-PF24 SIGNOR COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 t llicata Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6. SIGNOR-199254 0.2 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 0.41 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 0.494 TEK protein Q02763 UNIPROT MYOG protein P15173 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-241535 0.246 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 0.2 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI up-regulates quantity precursor of 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-268563 0.8 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. SIGNOR-62874 0.861 MMP13 protein P45452 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-272358 0.7 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 0.8 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 0.425 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 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-134620 0.767 WNT5B protein Q9H1J7 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 19577541 f fspada Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of ppargamma SIGNOR-186625 0.253 ROCK1 protein Q13464 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-100188 0.312 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 0.8 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262504 0.2 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys102 GVFICRGkEDALVTK 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275894 0.271 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 0.341 TBC1D4 protein O60343 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates 9606 12637568 f gcesareni These findings strongly indicate that insulin-stimulated phosphorylation of as160 is required for glut4 translocation and that this phosphorylation signals translocation through inactivation of the rab gap function. SIGNOR-99303 0.666 ETS2 protein P15036 UNIPROT IBSP protein P21815 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 t miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin SIGNOR-259873 0.2 CDK1 protein P06493 UNIPROT CC2D1A protein Q6P1N0 UNIPROT up-regulates activity phosphorylation Ser208 PASTPTYsPAPTQPA SIGNOR-C17 20171170 t nucleus lperfetto We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation. SIGNOR-268297 0.2 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Thr278 LARRRKAtQVGEKTP -1 8182057 t miannu The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells.‚  three VASP phosphorylation sites are phosphorylated by cAK and cGK. Thr, Ser I, and Ser 2 correspond to Thr278, Ser157, Ser239 of the VASP protein, respectively SIGNOR-250065 0.505 IRF8 protein Q02556 UNIPROT NCF2 protein P19878 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-222789 0.293 RPL10L protein Q96L21 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-262500 0.784 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 0.378 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 0.8 TCL1A protein P56279 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81680 0.825 BAZ2B protein Q9UIF8 UNIPROT H3-4 protein Q16695 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-266620 0.2 tetrabenazine chemical CHEBI:9467 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 8643547 t miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. SIGNOR-258491 0.8 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 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 25202122 t miannu During unperturbed cell cycles, DEC1 is a highly unstable protein that is targeted for proteasome-dependent degradation by the SCF(βTrCP) ubiquitin ligase in cooperation with CK1. SIGNOR-276853 0.346 Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 24311584 f miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. SIGNOR-263714 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763 12193595 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-244735 0.2 estramustine chemical CHEBI:4868 ChEBI MAP2 protein P11137 UNIPROT down-regulates activity chemical inhibition -1 1647395 t miannu Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. SIGNOR-259298 0.8 palbociclib chemical CHEBI:85993 ChEBI CCND2 protein P30279 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205701 0.8 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr199 AFLASPEyVNLPING 9606 BTO:0000150 19254954 t llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, SIGNOR-184379 0.437 CSNK1A1 protein P48729 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-73799 0.371 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183620 0.2 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 0.307 CHD2 protein O14647 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26895424 f miannu We show in mouse cells that the cNHEJ-dependent fusion of chromosomes containing uncapped telomeres requires the activity of CHD2. Together, these findings argue that the chromatin response mediated by CHD2 is triggered by the presence of DSBs and promotes repair of these lesions by the canonical KU-dependent NHEJ pathway. SIGNOR-264529 0.7 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser214 TVLTAQEsFSGSLGH -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276217 0.2 ROCK2 protein O75116 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 14701738 f 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-261712 0.7 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257974 0.8 RFX complex complex SIGNOR-C104 SIGNOR 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-254016 0.364 Glycine cleavage system complex SIGNOR-C437 SIGNOR carbon dioxide smallmolecule CHEBI:16526 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-268244 0.8 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Ser387 ETGLYRIsGCDRTVK 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-160398 0.303 COL3A1 protein P02461 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Collagen is the major structural protein in skeletal muscle ECM;... type III collagen appears to be more evenly distributed between endomysium and epimysium SIGNOR-254664 0.7 PTX3 protein P26022 UNIPROT CFH protein P08603 UNIPROT up-regulates activity binding 9606 19050261 t miannu Our findings identify PTX3 as a unique FH ligand in that it can bind both of the two hot-spots of FH, namely SCR7 and SCR19-20 and indicate that PTX3 participates in the localization of functionally active FH. PTX3 binds FH without interfering with its complement inhibitory function. Therefore PTX3 may contribute to focusing FH regulatory action, prevent excessive complement activation, and thus exert an important function in the control of inflammation in response to tissue injury. SIGNOR-252140 0.398 MAPK12 protein P53778 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser396 TFDSLPSsPSSATPH -1 12171600 t miannu We have also shown that JNK11, JNK22 and SAPK3 p38 phosphorylate eEF2 kinase very poorly at Ser-396 SIGNOR-250137 0.328 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 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/cdk3 SIGNOR-62357 0.718 FGR protein P09769 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276368 0.327 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo SIGNOR-259424 0.2 RAD21 protein O60216 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 20711430 f Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice SIGNOR-259975 0.7 GTF2I protein P78347 UNIPROT USF2 protein Q15853 UNIPROT up-regulates activity binding 9606 21282467 t lperfetto TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription SIGNOR-268537 0.347 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 0.385 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 0.2 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 0.592 EGFR protein P00533 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Tyr370 SLEISQSyTTTQRES -1 25601159 t miannu Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. SIGNOR-276872 0.399 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 0.2 DLG3 protein Q92796 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266005 0.2 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 0.647 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 0.378 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser484 IAVEYSDsEDDSSEF 9606 19012317 t gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. SIGNOR-182354 0.2 AKT1 protein P31749 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome. SIGNOR-252497 0.703 NFIL3 protein Q16649 UNIPROT NFIL3 protein Q16649 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-224248 0.2 EIF3F protein O00303 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-266395 0.925 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 0.8 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 0.2 CBL protein P22681 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by destabilization binding 9606 12496371 t miannu In our present study, we demonstrate that ligand-mediated stimulation causes EphA2 to be internalized and degraded. The mechanism of this response involves ligand-mediated autophosphorylation of EphA2, which promotes an association between EphA2 and the c-Cbl adaptor protein. We also show that c-Cbl promotes stimulation-dependent EphA2 degradation.  SIGNOR-272590 0.638 ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity relocalization 9606 20515759 t lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. SIGNOR-165786 0.908 UBE3A protein Q05086 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000007 28559284 t Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A SIGNOR-270946 0.307 PPP3CB protein P16298 UNIPROT 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-248364 0.614 Camostat mesylate chemical CID:5284360 PUBCHEM TMPRSS2 protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 32142651 t Monia Ndeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells, efficiently blocked 2019-nCoV-S-driven entry into Caco-2 (TMPRSS2+) but not 293T (TMPRSS2- 110 ) cells while the CatB/L inhibitor E64d had the opposite effect SIGNOR-261098 0.8 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 0.2 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248381 0.259 haloperidol chemical CHEBI:5613 ChEBI SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 17419803 t Simone Vumbaca These results suggest that haloperidol may irreversibly inactivate sigma-1 receptors in guinea pig and human cells, probably after metabolism to reduced haloperidol. SIGNOR-261090 0.8 RNF31 protein Q96EP0 UNIPROT NR0B1 protein P51843 UNIPROT up-regulates quantity by stabilization monoubiquitination 9606 BTO:0002588 19237537 t miannu RNF31 promotes monoubiquitination of DAX-1 in an RBR domain-dependent manner. In conclusion, our results suggest that the major DAX-1 modification observed in different experimental settings is likely to be monoubiquitination at one or more lysine residues (multiubiquitination) possibly located within the LBD of DAX-1. RNF31 stabilizes endogenous DAX-1. SIGNOR-271786 0.437 AKT1 protein P31749 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by stabilization phosphorylation Ser39 TTSTRTYsLGSALRP 9606 20856200 t llicata The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis. SIGNOR-252511 0.647 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 0.7 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 0.8 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1494 TLTRDYNsLTRSEHS 9606 15121854 t lperfetto Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures SIGNOR-124498 0.531 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251592 0.704 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity precursor of 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267553 0.8 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser202 PPTETGEsSQAEENI -1 1828073 t llicata Two serines located in the C-terminal end of neuromodulin, Ser-192 and Ser-193, were identified as the major casein kinase II phosphorylation sites. SIGNOR-250866 0.307 AURKB protein Q96GD4 UNIPROT SKA3 protein Q8IX90 UNIPROT up-regulates activity phosphorylation Ser159 SPRSPQLsDFGLERY -1 22371557 t miannu Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments. SIGNOR-262661 0.455 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 0.683 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 0.437 FAAP100 protein Q0VG06 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-263244 0.2 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr686 IITEYCRyGDLVDYL -1 19275932 t miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  SIGNOR-276142 0.527 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 0.296 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 0.452 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 0.418 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT up-regulates activity phosphorylation Ser326 QHPEMDFsKAKFN 9606 BTO:0000567 12852857 t lperfetto Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites. SIGNOR-103407 0.73 TSHB protein P01222 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t gcesareni Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners. SIGNOR-88653 0.722 PI-103 chemical CHEBI:90524 ChEBI PIK3C2B protein O00750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206160 0.8 SALL4 protein Q9UJQ4 UNIPROT CECR2 protein Q9BXF3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 33144328 t miannu SALL4 activates Cecr2 by directly binging to its promotor region and CECR2 in turn promotes reprogramming through forming a SMARCA1-contained chromatin remodeling complex with its DTT domain.  SIGNOR-263893 0.2 CNOT4 protein O95628 UNIPROT RBM15 protein Q96T37 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 26575292 t miannu We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4).  SIGNOR-271466 0.359 IRF1 protein P10914 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 f miannu Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1 SIGNOR-226481 0.38 PPP1R8 protein Q12972 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity binding 9606 phosphorylation:Thr416 EANSRCQtPIKMKPN 23241245 t Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1. SIGNOR-255665 0.36 ANP32A protein P39687 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 12522243 t PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. SIGNOR-259082 0.277 YARS1 protein P54577 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 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-270522 0.8 VARS1 protein P26640 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270529 0.8 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 0.753 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250805 0.345 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. We propose that under physiological conditions, phosphorylation of Smad3 by CDK inhibits its transcriptional activity, contributing to a decreased level of p15 and an increased level of c-Myc, thus facilitating cell cycle progression from G1 to S phase. SIGNOR-250750 0.743 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity binding 9606 33358571 t miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter SIGNOR-277684 0.588 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 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-252779 0.2 LRIG1 protein Q96JA1 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates ubiquitination 9606 16123311 t inferred from 70% of family members gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-269872 0.737 N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide chemical CHEBI:91332 ChEBI ROCK2 protein O75116 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 19740074 t miannu We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2. SIGNOR-262230 0.8 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 0.8 RAPGEF5 protein Q92565 UNIPROT NRAS protein P01111 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183738 0.436 NFKBIE protein O00221 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 BTO:0001271 12835716 t lperfetto Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe SIGNOR-217361 0.589 (-)-anisomycin chemical CHEBI:338412 ChEBI JUND protein P17535 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189672 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH11 protein P55287 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265829 0.8 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 0.819 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXRG protein P48443 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-256193 0.8 PLEKHA7 protein Q6IQ23 UNIPROT PDZD11 protein Q5EBL8 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 t Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33 SIGNOR-261253 0.38 C6 protein P13671 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263442 0.502 MMP13 protein P45452 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly906 EGPPGPQgLAGQRGI 9606 8609233 t miannu Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity. SIGNOR-256340 0.544 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation 9606 19433246 t miannu Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic. SIGNOR-268746 0.8 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 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-251148 0.446 PPM1D protein O15297 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity dephosphorylation 9606 23907458 t miannu Activating dephosphorylation of RUNX2 by Wip1 increases its transcriptional activity on the Bax promoter. SIGNOR-277110 0.444 HSPA9 protein P38646 UNIPROT MVD protein P53602 UNIPROT down-regulates activity binding 9534 12646231 t miannu Mortalin binds to mevalonate pyrophosphate decarboxyl ase in mammalian cell. Mot-2 inactivates MPD resulting in decreased amounts of the steady state Ras protein. SIGNOR-265890 0.342 CDON protein Q4KMG0 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235554 0.2 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser493 LSPRHRMsSPGVAGS 9606 BTO:0000801 29170386 t Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. SIGNOR-256098 0.246 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2114 RDIYKNDyYRKRGEG 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-154203 0.374 PRKAA1 protein Q13131 UNIPROT SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization phosphorylation Thr153 TLTHMSItRLHEQKL 27511885 t lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. SIGNOR-275864 0.2 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120152 0.311 MAPK1 protein P28482 UNIPROT PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 t lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. SIGNOR-249438 0.824 AMER1 protein Q5JTC6 UNIPROT APC protein P25054 UNIPROT up-regulates relocalization 9606 23151663 t gcesareni Apc membrane recruitment protein 1 (amer1;alsoknownas wtx) SIGNOR-199375 0.739 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 0.2 IKK-complex complex SIGNOR-C14 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression 9606 22056382 f Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation SIGNOR-253586 0.2 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 0.346 PINK1 protein Q9BXM7 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Ser424 DHDNDKEsDVEI 9606 25305081 t miannu PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.|PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. SIGNOR-279093 0.2 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 0.476 ALOX15 protein P16050 UNIPROT 15(S)-HETE smallmolecule CHEBI:15558 ChEBI up-regulates quantity chemical modification 9606 12517954 t lperfetto In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE SIGNOR-254094 0.8 CHMP4C protein Q96CF2 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-265528 0.643 NEDD4 protein P46934 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 19864419 t miannu Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability.  SIGNOR-271425 0.39 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 0.7 linifanib chemical CHEBI:91435 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193660 0.8 NR3C1 protein P04150 UNIPROT NR4A3 protein Q92570 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 f gcesareni We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors. SIGNOR-132309 0.291 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 0.329 AURKB protein Q96GD4 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 t miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. SIGNOR-276062 0.25 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 0.307 MAPK1 protein P28482 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t gcesareni In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. SIGNOR-94003 0.497 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity phosphorylation Ser2054 GGNKRKLsTAMALIG 10090 BTO:0000801 12196520 t miannu Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins. SIGNOR-250327 0.508 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 0.521 Gbeta proteinfamily SIGNOR-PF4 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-270080 0.2 IDE protein P14735 UNIPROT INS protein P01308 UNIPROT down-regulates quantity by destabilization cleavage -1 29596046 t SARA IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds SIGNOR-260986 0.719 WWC1 protein Q8IX03 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity 9606 BTO:0000007 20159598 f Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. SIGNOR-261954 0.442 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser159 EKLFRSQsADAPGPT -1 18480293 t miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation SIGNOR-262685 0.2 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 0.633 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR 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-264444 0.546 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 0.468 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 20978344 t inferred from family member miannu The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4) SIGNOR-267809 0.8 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 0.308 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 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-267770 0.8 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser390 KEAEEESsGGEEEDE 9606 BTO:0001938 11861906 t llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. SIGNOR-251070 0.379 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 0.435 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 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-252988 0.794 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 0.8 SDHD protein O14521 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 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-266274 0.927 beta-Funaltrexamine chemical CHEBI:81527 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-258773 0.8 RNF7 protein Q9UBF6 UNIPROT CDKN1B protein P46527 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-271447 0.348 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 0.2 ATM protein Q13315 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates activity phosphorylation Ser43 RNPEAALsPTFRSDS 32615088 t miannu Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. SIGNOR-265969 0.2 DEF6 protein Q9H4E7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 18976935 t lperfetto Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. SIGNOR-253369 0.392 XIAP protein P98170 UNIPROT OGT protein O15294 UNIPROT down-regulates quantity ubiquitination 9606 32994395 t miannu These results demonstrate that XIAP acts as an E3 ubiquitin ligase and ubiquitinates OGT in HCT116 colon cancer cells.|XIAP promotes the ubiquitin-dependent proteasomal degradation of OGT. SIGNOR-278800 0.2 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT up-regulates activity phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 t miannu In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation SIGNOR-262858 0.399 SOHLH1 protein Q5JUK2 UNIPROT ZP1 protein P60852 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 t Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. SIGNOR-266077 0.2 SIRT2 protein Q8IXJ6 UNIPROT KAT2B protein Q92831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12887892 t gcesareni Sir2 forms a complex with the acetyltransferase pcaf and myod and, when overexpressed, retards muscle differentiation. SIGNOR-104248 0.53 NCOA4 protein Q13772 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10347167 t miannu Identification of ara70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. / ppargamma and ara70 interact in the absence of the ppargamma ligand 15-deoxy-delta12,14-prostaglandin j2, although the addition of exogenous ligand enhances this interaction. SIGNOR-67687 0.449 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 0.266 fosinoprilat chemical CHEBI:116962 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 9187274 t miannu We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. SIGNOR-258613 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR CAD protein P27708 UNIPROT down-regulates activity phosphorylation Ser1406 GAGGRRLsSFVTKGY -1 17485345 t miannu The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.  SIGNOR-267442 0.2 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 0.61 citrate(3-) smallmolecule CHEBI:16947 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR down-regulates activity binding 9606 31751601 t miannu Once in the cytoplasm, citrate is able to inhibit phosphofructokinase 1 (PFK1) [4], the enzyme that is in charge of the “committed” step in glycolysis and converts fructose-6-phosphate to fructose-1, 6-bisphosphate (Fig. 1). In addition, citrate can inhibit PFK2, a bifunctional enzyme that regulates the rates of glycolysis and gluconeogenesis. Thus, a high level of citrate can lead to the reduction of glycolysis by directly inhibiting PFK1 and PFK2 and indirectly inhibiting PK. SIGNOR-267579 0.8 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 24239470 t miannu The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis SIGNOR-251531 0.901 STOML2 protein Q9UJZ1 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 18641330 t Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. SIGNOR-260377 0.2 HDAC1 protein Q13547 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-267738 0.753 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 BTO:0000562 12853467 t lperfetto These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor. SIGNOR-252464 0.654 ID1 protein P41134 UNIPROT CASK protein O14936 UNIPROT unknown binding 9606 15694377 t miannu We identified a novel CASK-interacting protein, inhibitor of differentiation 1 (Id1) SIGNOR-225149 0.405 CAMK2G protein Q13555 UNIPROT FLNA protein P21333 UNIPROT unknown phosphorylation Ser2523 VTGPRLVsNHSLHET BTO:0001141 11290523 t llicata Our TER experiments using a CaM peptide, which functions as a specific competitive inhibitor of nonmuscle filamin phosphorylation by CaM kinase II, strongly suggest that filamin phosphorylation is involved in endothelial cell barrier regulation, although the exact mechanism is not clear and consequent signaling events are not well understood.  SIGNOR-250696 0.428 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 0.399 BECN1 protein Q14457 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-260315 0.936 WNT7A protein O00755 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0003006 15705594 f Transfected Wnt-7a and Fzd-9 inhibit proliferation of NSCLC cells. SIGNOR-278114 0.7 SPDEF protein O95238 UNIPROT MMP9 protein P14780 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-255218 0.36 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser323 QRLFRSPsMPCSVIR 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-124843 0.2 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser481 KEDGHRTsTSAVPNL -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-250331 0.311 RAI1 protein Q7Z5J4 UNIPROT PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000614 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266841 0.386 TLR9 protein Q9NR96 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266748 0.439 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 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-258210 0.8 GPER1 protein Q99527 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates 9606 19549922 f gcesareni Gpr30 also stimulates the pi3k pathway, elevating cellular pip3 levels, which is also predicted to activate nr5a receptors by direct binding of pip3 to the ligand binding domain . SIGNOR-186206 0.8 Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273457 0.7 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 0.277 SP4 protein Q02446 UNIPROT CRX protein O43186 UNIPROT up-regulates activity binding 9606 15781457 t miannu Sp4 directly binds Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains. SIGNOR-225333 0.388 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 0.2 LMO3 protein Q8TAP4 UNIPROT ASCL1 protein P50553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21573214 f miannu Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. SIGNOR-254825 0.361 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 0.396 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 10090741 t miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. SIGNOR-250172 0.429 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256350 0.695 PPP3CB protein P16298 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-248363 0.252 MTA1 protein Q13330 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001211 22184117 f miannu The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. SIGNOR-254242 0.288 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192895 0.8 RBP2 protein P50120 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity relocalization 9606 31963453 t lperfetto Either acting on the producing cell (autocrine signaling) or the receiving cell (paracrine signaling), RA is transferred into the nucleus by Cellular retinoic acid-binding protein 2 (CRABP2) [18]. Once inside the nucleus, RA binds to specific nuclear transcription factors named Retinoic acid receptors (RARs) SIGNOR-265130 0.8 TGFB1 protein P01137 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000764 20846954 f Regulation miannu We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. SIGNOR-251922 0.367 H4C1 protein P62805 UNIPROT Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 t lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-265311 0.2 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA12 protein Q03113 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t inferred from 70% family members milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-269968 0.2 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser278 VDTGITNsQTLIPDC 9606 10839544 t lperfetto We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. SIGNOR-78025 0.856 GNG12 protein Q9UBI6 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000586 16293724 t gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-141795 0.4 SRC protein P12931 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 9792645 t llicata C-src phosphorylates IkappaB On tyrosine 42|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. SIGNOR-60879 0.688 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572;BTO:0000801 SIGNOR-C14 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-235400 0.922 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT up-regulates activity phosphorylation Thr134 KKVRKPRtIYSSYQL -1 11343707 t lperfetto Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. SIGNOR-249097 0.307 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277176 0.2 LYN protein P07948 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 t Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b SIGNOR-251398 0.678 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Tyr4473 VEIGNPTyKMYEGGE 9606 18381291 t lperfetto The observation that the wild type protein was phosphorylated to a higher level than the y4473f mutant again indicates that phosphorylation of the tyr4473 residue by v-src is occurring in these cellsmutation of tyr4473 to alanine, which abolishes snx17 binding, resulted in impaired receptor recycling and reduced amounts of the mature form of lrp1 on the cell surface SIGNOR-178159 0.394 PRKG1 protein Q13976 UNIPROT PPP1R17 protein O96001 UNIPROT up-regulates phosphorylation Thr119 KKPRRKDtPALHMSP 9606 BTO:0001011 10051666 t miannu Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. SIGNOR-263147 0.656 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 0.698 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 0.2 RPS6KB1 protein P23443 UNIPROT 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-102051 0.96 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 0.583 MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 9430721 t Luana The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms SIGNOR-260721 0.744 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001757 12202832 t gcesareni We investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character. SIGNOR-174432 0.8 MAPK1 protein P28482 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-184172 0.335 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 0.7 AP1 complex SIGNOR-C154 SIGNOR CCL2 protein P13500 UNIPROT up-regulates activity transcriptional regulation 9606 21561061 t Luana 3b Potentiates AP-1-Dependent MCP-1 Promoter Activity SIGNOR-260764 0.616 SNAP91 protein O60641 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-264114 0.633 NEDD4 protein P46934 UNIPROT LAPTM5 protein Q13571 UNIPROT up-regulates activity ubiquitination 9606 17116753 t miannu These results suggest that LAPTM5 ubiquitination is mediated by Nedd4.|Thus, Nedd4 promotes the recruitment of GGA3 to LAPTM5, allowing LAPTM5 translocation from the Golgi to the lysosome with the aid of GGA3. SIGNOR-278768 0.476 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 0.8 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 0.365 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 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC3 protein Q13489 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-64103 0.668 GSK3B protein P49841 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates quantity by stabilization phosphorylation Ser256 LRRAIQLsMQGSSRN 9606 BTO:0000007 17434145 t lperfetto Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3| SIGNOR-264821 0.465 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 0.333 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 0.7 EEF1A1P5 protein Q5VTE0 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269551 0.8 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 0.2 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 0.945 NEDD4L protein Q96PU5 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253464 0.283 MIF protein P14174 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 16636133 f Regulation of expression miannu MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells. SIGNOR-251832 0.2 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257446 0.8 MAPK1 protein P28482 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-120120 0.311 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr356 GTRSRSHtSEGTRSR 9606 18787837 t llicata Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1. SIGNOR-180825 0.569 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser554 PDSEASQsPQYSFES 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-84992 0.441 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified. SIGNOR-266464 0.8 metformin chemical CHEBI:6801 ChEBI CRTC2 protein Q53ET0 UNIPROT down-regulates 9606 20577053 f gcesareni It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm SIGNOR-166361 0.8 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 0.2 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser198 IRTHLSQsPRVPSKC 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248525 0.259 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Thr1065 AKRPRVGtPLATEDS 9606 BTO:0001109 28945223 t miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  SIGNOR-276744 0.2 FYN protein P06241 UNIPROT DCC protein P43146 UNIPROT up-regulates activity phosphorylation Tyr1420 TEDSANVyEQDDLSE 10090 BTO:0001909 15557120 t miannu Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo. SIGNOR-268176 0.572 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 0.345 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 0.2 TLN1 protein Q9Y490 UNIPROT AM/b2 integrin complex SIGNOR-C170 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-257620 0.584 beta-Funaltrexamine chemical CHEBI:81527 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-258771 0.8 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 0.4 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 0.518 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 0.2 ATP7A protein Q04656 UNIPROT SOD3 protein P08294 UNIPROT up-regulates activity 10090 29301787 t lperfetto Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide. SIGNOR-272267 0.696 mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-256064 0.7 CAMK2A protein Q9UQM7 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr574 VDNIRSAtPEALAFV 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-96628 0.372 PRKCB protein P05771 UNIPROT CFLAR protein O15519 UNIPROT up-regulates quantity by stabilization phosphorylation Ser193 LQAAIQKsLKDPSNN 9606 BTO:0000664 19343040 t miannu  Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins SIGNOR-276146 0.2 HHIP protein Q96QV1 UNIPROT SHH protein Q15465 UNIPROT down-regulates activity binding 10090 10050855 t lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. SIGNOR-65078 0.897 NMDA receptor_2B complex SIGNOR-C348 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 t miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  SIGNOR-264219 0.8 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 0.2 naproxen chemical CHEBI:7476 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-258603 0.8 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 0.464 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9575217 t lperfetto Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-249507 0.866 PIM1 protein P11309 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 16146838 f lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-256657 0.7 NEDD4L protein Q96PU5 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by destabilization ubiquitination 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-251948 0.775 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. SIGNOR-250893 0.33 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 20181957 t miannu P53 directly induces the expression of Siah-1 and in turn formation of a unique SCF-like complex (SCF(TBL1)) comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin β-like 1 (TBL1), and APC SIGNOR-271953 0.372 SLC44A2 protein Q8IWA5 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 12761501 f Giorgia Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways SIGNOR-260390 0.2 MSI1 protein O43347 UNIPROT NUMB protein P49757 UNIPROT down-regulates binding 9606 20477901 t Inhibits translation gcesareni The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch . SIGNOR-165617 0.445 RFC1 protein P35251 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-265505 0.864 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 0.283 IL6 protein P05231 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 10116 BTO:0001103 23869758 f andrea cerquone perpetuini IL-6 induced dose-dependent increase in satellite cell proliferation by activating the JAK2/STAT3/cyclin D1 pathway.Treatment with 1 ng/ml IL-6 for 3 h significantly increased p-STAT3+/MyoD+ cell numbers by 44% compared to control media only . SIGNOR-255415 0.756 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 0.781 POU5F1 protein Q01860 UNIPROT DKK1 protein O94907 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-254934 0.349 TTI1 protein O43156 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 t miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. SIGNOR-272004 0.65 DLG3 protein Q92796 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270885 0.512 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 11583623 t amattioni Xiap is an endogenous inhibitor of caspase-3 SIGNOR-110837 0.939 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK1 protein P39086 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264470 0.8 L-serine chemical CHEBI:17115 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity chemical activation 9606 23064226 t inferred from family member We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. SIGNOR-270286 0.8 IKBKE protein Q14164 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0000551 23691078 t lperfetto Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation. SIGNOR-252949 0.407 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr323 DEPVADPyDQSFESR 9606 15735648 t fstefani T cell src family kinases and zap70 activate p38 by phosphorylating tyr323. SIGNOR-134293 0.489 IKZF1 protein Q13422 UNIPROT Lymphopoiesis phenotype SIGNOR-PH111 SIGNOR up-regulates activity 9606 BTO:0000725 25085254 f The Ikaros family of DNA binding proteins are critical regulators of lymphocyte differentiation. In multipotent hematopoietic progenitors, Ikaros supports transcriptional priming of genes promoting lymphocyte differentiation. SIGNOR-259958 0.7 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 0.2 FIP1L1 protein Q6UN15 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 14749727 t miannu 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-121649 0.901 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 0.8 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t 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-169654 0.64 SMO protein Q99835 UNIPROT GATA3 protein P23771 UNIPROT up-regulates activity 17139329 t fferrentino That GATA is a downstream effector of the hedgehog pathway. SIGNOR-253527 0.2 ITGA4 protein P13612 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-253293 0.858 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 0.581 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 10737616 t lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. SIGNOR-249417 0.566 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120080 0.789 TTK protein P33981 UNIPROT USP16 protein Q9Y5T5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr554 EVLTSSPtRNLNGAY 9606 BTO:0002181 28380042 t miannu  Usp16 is a TTK phosphorylation substrate.  SIGNOR-277351 0.37 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT down-regulates activity dephosphorylation Tyr730 DMKPGVSyVVPTKAD -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254710 0.2 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 0.791 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr821 KISEGLPtPTKMTPR 9606 SIGNOR-C83 9139732 t miannu 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-47895 0.884 CSNK2B protein P67870 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser575 AGESLDQsMEEEEEE 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-251063 0.327 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Ser224 EKSYRHRsAFIVHKR 9606 BTO:0002552 31399647 t miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. SIGNOR-276755 0.2 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 0.792 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 0.7 terazosin chemical CHEBI:9445 ChEBI ADRA1B protein P35368 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-258669 0.8 RNF31 protein Q96EP0 UNIPROT CASP1 protein P29466 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0005111 32122970 t miannu HOIP forms a constitutive interaction with caspase-1 and mediates the linear ubiquitination of the CARD pro-domain. Upon engagement of apoptosis, caspase-1 and caspase-8 cleave HOIP at Asp-348 and Asp-387, limiting the ability of LUBAC to ubiquitinate substrates. SIGNOR-272191 0.2 wortmannin chemical CHEBI:52289 ChEBI MYLK protein Q15746 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207791 0.8 SRC protein P12931 UNIPROT FHIT protein P49789 UNIPROT up-regulates activity phosphorylation Tyr114 FHRNDSIyEELQKHD -1 15835917 t lperfetto The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit. SIGNOR-247134 0.466 tamsulosin chemical CHEBI:9398 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258470 0.8 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR DUSP1 protein P28562 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001103 17158101 f Andrea Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis SIGNOR-255744 0.275 BRCA1 protein P38398 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity binding -1 phosphorylation: ser1263 FSDSPPQsPTFPEAG 16698035 t ACCA binds BRCA1 when phosphorylated onSer1263, thus supporting a model in which controlof lipid synthesis would be mediated at least in part,viaphosphorylation of the Ser1263. SIGNOR-267474 0.548 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 0.7 ABL2 protein P42684 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr686 IITEYCRyGDLVDYL -1 19275932 t miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  SIGNOR-276140 0.303 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 0.7 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 0.579 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI KDR protein P35968 UNIPROT down-regulates 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-258111 0.8 PTPRJ protein Q12913 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 12062403 t Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021 SIGNOR-248704 0.582 RUNX2 protein Q13950 UNIPROT COL1A2 protein P08123 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-107166 0.427 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 0.7 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 0.76 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 0.637 Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT up-regulates activity cleavage Asp27 DDLFFEAdGPKQMKC -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-256375 0.803 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr665 KEQNRELySEGLGAW 26319181 t lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. SIGNOR-275920 0.506 MTNR1B protein P49286 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-256850 0.452 MAPK14 protein Q16539 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR -1 9543386 t miannu P38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. SIGNOR-250091 0.439 ECM stimulus SIGNOR-ST20 SIGNOR A11/b1 integrin complex SIGNOR-C168 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-259050 0.7 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 0.778 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186788 0.274 CSNK2A1 protein P68400 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates phosphorylation Ser2 sGDEMIFD 9606 BTO:0000567 16225457 t lperfetto The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals. SIGNOR-140994 0.35 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1675 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-269374 0.726 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 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-209992 0.8 GIGYF2 protein Q6Y7W6 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 20670374 t miannu We demonstrated that, in cultured cells and mammalian brains, GIGYF2 interacts and colocalises with Grb10, promoting ligand‐induced ubiquitination of IGF‐1R, and thereby regulates receptor degradation SIGNOR-260057 0.596 RPL11 protein P62913 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 25301064 t miannu We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73 SIGNOR-205514 0.359 bosutinib chemical CHEBI:39112 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-259271 0.8 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 0.7 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates activity phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000007 9512493 t lperfetto The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells. SIGNOR-248996 0.546 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Tyr934 PAHASDEiYEIMQKC 9606 19275932 t Manara C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) | 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-260931 0.527 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 0.314 CDK5/CDK5R1 complex SIGNOR-C144 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-251601 0.704 GATA1 protein P15976 UNIPROT ZNF268 protein Q14587 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 22235304 f miannu Here we found that gata-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of znf268 SIGNOR-195410 0.371 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 0.689 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 0.582 CNR1 protein P21554 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257346 0.25 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 0.8 PAK1 protein Q13153 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 12876277 t lperfetto We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation. SIGNOR-244924 0.582 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser985 SNVSPAIsIHEIGAV -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-250282 0.2 NFASC protein O94856 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266717 0.745 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 0.2 LPAR2 protein Q9HBW0 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-257257 0.25 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 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-248626 0.893 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 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-244160 0.2 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 t gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-33133 0.72 SPRY1 protein O43609 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates binding 9606 11585837 t gcesareni Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway. SIGNOR-110948 0.386 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 0.7 SMARCB1 protein Q12824 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-270755 0.839 CDK4 protein P11802 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by destabilization phosphorylation Ser105 AYTPPPVsPRFSFPG 9606 BTO:0000567 21447557 t miannu Finally, CDK4 phosphorylated GATA4 directly, which promoted the degradation of GATA4 in cultured cells. SIGNOR-276317 0.356 E2F1 protein Q01094 UNIPROT HDAC1 protein Q13547 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-199952 0.653 ITGB4 protein P16144 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257720 0.584 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 0.3 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Thr216 RSSSSEStGTPSNPD 9606 11983168 t fstefani Cyclin g also binds in vivo and in vitro to mdm2 and markedly stimulates the ability of pp2a to dephosphorylate mdm2 at t216. Our data imply that the function of cyclin g is to serve as a negative regulator of p53 by activating mdm2 through dephosphorylation. SIGNOR-86736 0.4 CSNK2B protein P67870 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-200806 0.246 PRKG2 protein Q13237 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 10531334 t gcesareni Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps SIGNOR-71751 0.53 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 0.446 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 0.502 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates activity phosphorylation 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-251510 0.845 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 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-255353 0.453 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 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t lperfetto Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-244699 0.2 carbachol chemical CHEBI:3385 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258620 0.8 CDK11A protein Q9UQ88 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser174 TPAVPPVsEDEDDDD 19520772 t lperfetto CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression|We show that PAK1 is a substrate of CDK11p58 and can be strongly activated upon phosphorylation. SIGNOR-273026 0.384 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates chemical inhibition 9606 SIGNOR-C15 21399626 t gcesareni Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive SIGNOR-172822 0.8 ATM protein Q13315 UNIPROT WRAP53 protein Q9BUR4 UNIPROT up-regulates activity phosphorylation Ser64 PVAGSAVsQELREGD 9606 BTO:0001938 27715493 t done miannu Here, we show that in response to various types of DNA damage, including IR and UV, WRAP53β is phosphorylated on serine residue 64 by ATM with a time-course that parallels its accumulation at DNA lesions. Interestingly, recruitment of phosphorylated WRAP53β (pWRAP53βS64) to sites of such DNA damage promotes its interaction with γH2AX at these locations.  SIGNOR-273511 0.337 MAPK14 protein Q16539 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser7 sPAPLSPL 9606 22128155 t gcesareni Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin SIGNOR-177927 0.521 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR PDGFA protein P04085 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-251567 0.2 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 0.2 P2RY11 protein Q96G91 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-257386 0.385 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 12586835 t gcesareni The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424). SIGNOR-98215 0.384 SLBP protein Q14493 UNIPROT H3-4 protein Q16695 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-265417 0.2 MMP26 protein Q9NRE1 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272370 0.7 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 0.369 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G2 protein P78344 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-269156 0.386 TLN1 protein Q9Y490 UNIPROT ITGB4 protein P16144 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257627 0.494 pazopanib hydrochloride chemical CHEBI:71217 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. SIGNOR-259168 0.8 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 0.569 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 0.445 CIB2 protein O75838 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 9606 35408910 t miannu So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles. SIGNOR-269668 0.2 PRKD3 protein O94806 UNIPROT GIT1 protein Q9Y2X7 UNIPROT unknown phosphorylation Ser46 RSLGRHIsIVKHLRH 9606 22893698 t lperfetto We propose that phosphorylation of git1 on serine 46 by pkd3 represents a molecular switch by which git1 localization, paxillin trafficking, and cellular protrusive activity are regulated. SIGNOR-191839 0.361 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 BTO:0000007 22863277 f inferred from 70% of family members milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-269864 0.8 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266509 0.8 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-273159 0.384 Laminin-5 complex SIGNOR-C184 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-253219 0.548 PTPN13 protein Q12923 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 19307596 t miannu Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1 dependent dephosphorylation of Src at the activation loop.|Our results reveal a novel Src inactivation cycle in which reversion-induced LIM preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src. SIGNOR-277125 0.54 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 0.328 LRSAM1 protein Q6UWE0 UNIPROT TSG101 protein Q99816 UNIPROT down-regulates quantity monoubiquitination 9606 BTO:0000007 15256501 t miannu Tal increases ubiquitylation of Tsg101 and affects its solubility in a RING- and PTAP-dependent manner.  Tal-mediated ubiquitylation of Tsg101 inactivates this sorting function and concomitantly translocates Tsg101 from relatively insoluble membrane subdomains. Presumably, the coordinated action of Tal and a deubiquitylation enzyme (DUB) enables recycling of Tsg101 and reloading of cargo. SIGNOR-271509 0.527 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 9099746 t lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1 SIGNOR-47162 0.405 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 0.8 GTF2H1 protein P32780 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269316 0.905 CHAMP1 protein Q96JM3 UNIPROT MAD2L2 protein Q9UI95 UNIPROT up-regulates activity binding 9606 21063390 t miannu Here, we report a novel regulator for accurate chromosome segregation, chromosome alignment-maintaining phosphoprotein (CAMP). We identified CAMP as a MAD2L2-interacting protein. Spindle localization of MAD2L2 was abrogated by CAMP depletion (Supplementary Figure S2A) SIGNOR-264904 0.497 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271365 0.2 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 0.393 EIF2B2 protein P49770 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269125 0.802 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 0.2 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120052 0.789 seliciclib chemical CHEBI:45307 ChEBI TP53 protein P04637 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206577 0.8 HAUS6 protein Q7Z4H7 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 f miannu FAM29A interacts with the NEDD1-gamma-tubulin complex and recruits this complex to the spindle, which, in turn, promotes MT polymerization. SIGNOR-261420 0.7 Caspase 8 complex complex SIGNOR-C231 SIGNOR 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-256473 0.48 L-serine chemical CHEBI:17115 ChEBI PKM protein P14618 UNIPROT up-regulates activity chemical activation 9606 23064226 t We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. SIGNOR-251557 0.8 GFI1 protein Q99684 UNIPROT CYP27B1 protein O15528 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15947108 f miannu Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells. SIGNOR-254205 0.2 RFX complex complex SIGNOR-C104 SIGNOR HLA-DMA protein P28067 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-253993 0.327 DDHD2 protein O94830 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-269652 0.8 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 0.7 COX5B protein P10606 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253102 0.7 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 0.7 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation 9606 20208177 t Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation SIGNOR-251664 0.732 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 0.406 NMDA receptor_2A complex SIGNOR-C347 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-264132 0.7 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 0.67 WNT6 protein Q9Y6F9 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-176193 0.462 FHIT protein P49789 UNIPROT AKT2 protein P31751 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis SIGNOR-143703 0.249 risperidone chemical CHEBI:8871 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-258525 0.8 LTB4R protein Q15722 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-257086 0.435 RASSF1 protein Q9NS23 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR 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-269950 0.806 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1716180 t lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. SIGNOR-21324 0.485 GAPDH protein P04406 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-266494 0.8 CSNK2A1 protein P68400 UNIPROT NKX2-5 protein P52952 UNIPROT up-regulates activity phosphorylation Ser164 FKQQRYLsAPERDQL 9534 BTO:0004055 9858576 t llicata Mutational analysis and in vitro kinase assays suggested that this 40-kDa Csx/Nkx2.5 kinase is a catalytic subunit of casein kinase II (CKII) that phosphorylates the serine residue between the first and second helix of the homeodomain. This CKII site is phosphorylated in vivo. CKII-dependent phosphorylation of the homeodomain increased Csx/Nkx2. 5 DNA binding. Serine-to-alanine mutation at the CKII phosphorylation site reduced transcriptional activity when the carboxyl-terminal repressor domain was deleted. SIGNOR-250924 0.332 SLBP protein Q14493 UNIPROT H2AJ protein Q9BTM1 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-265412 0.2 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 0.85 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-145128 0.432 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 0.786 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 0.8 XRCC6 protein P12956 UNIPROT PRKDC protein P78527 UNIPROT up-regulates relocalization 9606 19133841 t gcesareni Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack. SIGNOR-183276 0.94 CAMK2A protein Q9UQM7 UNIPROT CD44 protein P16070 UNIPROT up-regulates activity phosphorylation Ser706 LNGEASKsQEMVHLV 9606 BTO:0000452 11463356 t lperfetto In previous studies we have demonstrated that a key control point for this receptor is the phosphorylation of CD44 on a conserved cytoplasmic serine residue, Ser(325). This modification is not required for efficient ligand binding, but is an essential component of CD44-dependent cell migration on a hyaluronan substratum. We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase. SIGNOR-109502 0.2 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 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-201486 0.67 PKNOX1 protein P55347 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20864515 f miannu Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. SIGNOR-254924 0.2 FANCD2 protein Q9BXW9 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates activity binding 9606 BTO:0005035 phosphorylation:Ser331 KSKGRASsSGNQESS 19861535 t lperfetto Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction SIGNOR-263238 0.812 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 15284220 t gcesareni In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2. SIGNOR-127354 0.506 3-[8-amino-1-(2-phenyl-7-quinolinyl)-3-imidazo[1,5-a]pyrazinyl]-1-methyl-1-cyclobutanol chemical CHEBI:91402 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193675 0.8 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 t lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. SIGNOR-252872 0.765 AMPK complex SIGNOR-C15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates 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 phosphorylation sites, resulting in foxo activation SIGNOR-216484 0.352 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser37 EDLTDELsLNKISAD -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276207 0.2 MSN protein P26038 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-173647 0.318 MAPK10 protein P53779 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. SIGNOR-124001 0.26 TRIM23 protein P36406 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003682 19176615 t miannu We show here that the upregulation of NF-kappaB by UL144 is dependent upon cellular tripartite motif 23 (TRIM23) protein. We propose a mechanism by which UL144 activates NF-kappaB through a direct interaction with the cellular protein TRIM23 in a complex containing TRAF6. we propose that TRIM23 mediates TRAF6 autoubiquitination in the presence of UL144, resulting in the virally controlled activation of NF-κB stimulation at early times of HCMV infection. SIGNOR-266655 0.313 CDK1 protein P06493 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 t lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. SIGNOR-103242 0.364 PLCB1 protein Q9NQ66 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256497 0.8 EMX1 protein Q04741 UNIPROT NRP1 protein O14786 UNIPROT up-regulates quantity by expression transcriptional regulation -1 26534986 t Luana EMX1 activates the transcription of Nrp1 in vitro. SIGNOR-261593 0.2 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 0.2 WWP1 protein Q9H0M0 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25071155 t miannu WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  SIGNOR-272232 0.283 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 0.7 SIRT7 protein Q9NRC8 UNIPROT RAN protein P62826 UNIPROT down-regulates activity deacetylation Lys37 HLTGEFEkKYVATLG 31075303 t Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV lperfetto N this study, we demonstrated that SIRT7 interacts with a small GTPase, Ras-related nuclear antigen (Ran), and deacetylates Ran at K37. |The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins [[18], [19], [20]]. Interestingly, Ran is a lysine-acetylated protein SIGNOR-275849 0.2 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 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-258921 0.8 IL22 protein Q9GZX6 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 12941475 t fspada In addition, il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4. SIGNOR-86340 0.893 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 0.446 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 0.529 MEF2A protein Q02078 UNIPROT MYH10 protein P35580 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-238763 0.317 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267529 0.8 SOX6 protein P35712 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26893351 t We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST SIGNOR-255824 0.292 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 0.7 MYC protein P01106 UNIPROT CDK4 protein P11802 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-102734 0.569 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 0.341 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT 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-163676 0.2 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 0.703 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 0.767 nitrendipine chemical CHEBI:7582 ChEBI KCNN4 protein O15554 UNIPROT down-regulates activity chemical inhibition 9606 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-258831 0.8 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 0.504 CDK1 protein P06493 UNIPROT RAB1A protein P62820 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 1902553 t Giulio We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells. SIGNOR-261284 0.526 FOXO proteinfamily SIGNOR-PF27 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 f gcesareni Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. SIGNOR-252932 0.7 Caspase 8 complex complex SIGNOR-C231 SIGNOR 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-256443 0.879 SMARCB1 protein Q12824 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270725 0.754 TBR1 protein Q16650 UNIPROT AUTS2 protein Q8WXX7 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 20615956 t miannu Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. SIGNOR-266836 0.359 CFH protein P08603 UNIPROT CRP protein P02741 UNIPROT down-regulates activity binding 9606 BTO:0004910 26961257 t miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. SIGNOR-252145 0.551 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274074 0.66 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1542 EEQQLEEsGPHDLTE 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72072 0.819 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 0.822 TAP1 protein Q03518 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity relocalization 9606 31810556 t scontino Following cytosolic proteolysis, antigenic peptides are recruited to the ER and translocated to its lumen by the Transporter associated with Antigen Processing (TAP). SIGNOR-267778 0.8 PHA-680632 chemical CID:11249084 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206097 0.8 IL1RL1 protein Q01638 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 t miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  SIGNOR-277704 0.655 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 0.8 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 0.511 A4/b1 integrin complex SIGNOR-C162 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression 10090 25786978 f lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253287 0.302 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 0.704 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 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR 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-253667 0.264 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr457 YVSPRIStPQTNTVP 9606 BTO:0000567 30021153 t lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. SIGNOR-265035 0.2 ARHGAP4 protein P98171 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260460 0.479 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 0.753 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 0.2 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 0.7 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235499 0.788 AKT1 protein P31749 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 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-259405 0.2 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser346 DRSDIESsSDEEDSE 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-273992 0.2 CRX protein O43186 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 f miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. SIGNOR-253815 0.368 RRAGC protein Q9HB90 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-228173 0.793 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser174 LRKGTLGsKGQKTTQ -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-273492 0.267 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 0.8 LCK protein P06239 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 17998336 t gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. SIGNOR-159168 0.566 OTUB1 protein Q96FW1 UNIPROT UBE2N protein P61088 UNIPROT down-regulates binding 9606 21763684 t gcesareni The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13 SIGNOR-175050 0.704 ULK1 protein O75385 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit. SIGNOR-173050 0.505 IL12A protein P29459 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni Like il-12, il-23 binds to the il-12r subunit il-12rbeta1. SIGNOR-87677 0.572 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 0.923 zolmitriptan chemical CHEBI:10124 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258341 0.8 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 0.583 CAMK2A protein Q9UQM7 UNIPROT ID1 protein P41134 UNIPROT up-regulates activity phosphorylation Ser36 GEVVRCLsEQSVAIS 9606 BTO:0001620 29079782 t miannu Here we show that CaMKII can directly phosphorylate Beclin 1 at Ser90 to promote K63-linked ubiquitination of Beclin 1 and activation of autophagy. SIGNOR-277367 0.2 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR3 protein Q9UBY5 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-257530 0.8 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000142 10980603 t gcesareni Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress, SIGNOR-81541 0.362 TSC22D3 protein Q99576 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000007 11468175 t GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. SIGNOR-253299 0.358 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 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-264520 0.2 Ku-0063794 chemical CHEBI:85572 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000887;BTO:0001260 20884880 t gcesareni Sgk-1 activation in response to stretch is blocked by insulin-like growth factor (igf)-1 receptor inhibitor and mammalian target of rapamycin complex (mtorc)2 inhibitor (ku-0063794) but not mtorc1 inhibitor (rapamycin). SIGNOR-168188 0.8 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 0.42 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271811 0.8 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 0.2 SF3B3 protein Q15393 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268405 0.932 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 0.2 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 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNB1 protein Q02641 UNIPROT up-regulates activity phosphorylation Ser348 IVYIKITsPKVLQRL 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-262965 0.2 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 0.932 EIF2B3 protein Q9NR50 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269136 0.735 SALL4 protein Q9UJQ4 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21526180 f miannu we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples SIGNOR-255122 0.265 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230396 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-67392 0.434 RUNX1 protein Q01196 UNIPROT GP1BA protein P07359 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-254195 0.402 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120040 0.789 PKA proteinfamily SIGNOR-PF17 SIGNOR NR5A2 protein O00482 UNIPROT up-regulates activity phosphorylation Ser510 LPEIRAIsMQAEEYL 9606 BTO:0000093 16109788 t miannu  PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469.  SIGNOR-276041 0.2 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser233 ARLHTKPsQAPAVEV 9606 BTO:0000007 27829214 t miannu PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1.  SIGNOR-273506 0.2 VARS1 protein P26640 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270528 0.8 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 0.7 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR ATF2 protein P15336 UNIPROT up-regulates activity binding 9606 10085140 t lperfetto Here we report that the transcription factor atf-2 (also called cre-bp1) is bound by a hetero-oligomer of smad3 and smad4 upon tgf-beta stimulation. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. SIGNOR-65583 0.598 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser64 PRGRPKGsKNKGAAK 9606 10617144 t fspada In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64 SIGNOR-73610 0.263 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 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 0.342 COL1A2 protein P08123 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253248 0.48 MEIS1 protein O00470 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255865 0.7 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 0.418 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-167184 0.926 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 0.8 TRHR protein P34981 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 23248581 t scontino TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ). SIGNOR-267202 0.491 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr650 PMELEPMySNVNPGD -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-274008 0.2 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 0.8 ULK3 protein Q6PHR2 UNIPROT GLI1 protein P08151 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. | Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins. SIGNOR-260797 0.673 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270395 0.8 MAPK8 protein P45983 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation. SIGNOR-145297 0.464 RPL36 protein Q9Y3U8 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-262464 0.856 SLC38A9 protein Q8NBW4 UNIPROT leucine smallmolecule CHEBI:25017 ChEBI up-regulates quantity relocalization 9606 29053970 t SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins SIGNOR-255313 0.8 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 0.2 KDM6A protein O15550 UNIPROT HOXC6 protein P09630 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260028 0.26 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 15886098 t amattioni Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations. SIGNOR-136958 0.695 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 0.709 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 0.845 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe635 HHQKLVFfAEDVGSN -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261774 0.489 MYOG protein P15173 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates activity binding 9534 19631210 t llicata Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin. SIGNOR-237854 0.512 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 0.539 CDC73 protein Q6P1J9 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 16630820 t gcesareni Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo SIGNOR-146282 0.695 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 0.481 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 0.482 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 0.8 Vincristine sulfate chemical CHEBI:79401 ChEBI FN1 protein P02751 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-259252 0.8 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 0.311 imatinib methanesulfonate chemical CHEBI:31690 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;VIRAL ABL gcesareni SIGNOR-193387 0.8 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249484 0.886 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 17601773 t lperfetto Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-217312 0.337 PTP4A3 protein O75365 UNIPROT EZR protein P15311 UNIPROT down-regulates activity dephosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0001109 18078820 t Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action. SIGNOR-248342 0.277 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE11A protein Q9HCR9 UNIPROT up-regulates activity phosphorylation Ser162 RALLRKAsSLPPTTA -1 18312413 t miannu The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold. SIGNOR-276179 0.2 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser553 KNAHAKAsRTSSKHK 9606 BTO:0002181 21177494 t miannu  PKGII directly phosphorylated and stimulated SHP-1 activity SIGNOR-276288 0.2 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248927 0.486 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 0.2 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 0.7 ULK1 protein O75385 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser88 LVMNMLKsSFATCVL 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-274031 0.2 ATP8B1 protein O43520 UNIPROT ATP2B2 protein Q01814 UNIPROT up-regulates 9606 BTO:0000630 19478059 f lperfetto Consequently ATP8B1 deficiency, with a secondary disturbance of membrane lipid asymmetry, likely inhibits PMCA2 activity and affects the efficiency of mechanotransduction. SIGNOR-262584 0.2 IRX1 protein P78414 UNIPROT RALGPS1 protein Q5JS13 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-261668 0.2 RPS7 protein P62081 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-262417 0.82 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 0.32 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 0.732 MAP3K11 protein Q16584 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 9003778 f gcesareni The kinase-inactive mlk-3 failed to activate sapk, demonstraiting that mlk-3 catalytic activity is necessary for the induction of the sapk pathway. SIGNOR-45791 0.626 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 8537411 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-39433 0.551 AKT proteinfamily SIGNOR-PF24 SIGNOR FAS protein P25445 UNIPROT down-regulates 9606 15004527 f gcesareni Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27 SIGNOR-123239 0.2 ADCK5 protein Q3MIX3 UNIPROT SOX9 protein P48436 UNIPROT up-regulates activity phosphorylation Ser181 YQPRRRKsVKNGQAE 32277958 t lperfetto Here we investigated the mechanism of ADCK5 involved in regulating invasion and migration of lung cancer cells, and showed that ADCK5 might regulate the expression of tumor oncogene human pituitary tumor transforming gene-1 (PTTG1) by phosphorylating transcription factor SOX9|Mutagenesis of potential serine phosphorylation sites on SOX9 indicated that serine 181 might be required to maintain transcription activation of SOX9 as well as increase PTTG1 levels. SIGNOR-264567 0.2 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 0.272 F12 protein P00748 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-261856 0.472 ATM protein Q13315 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates activity phosphorylation Ser26 LRGNPSSsQVDEEQM 9606 BTO:0002137 26774286 t In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7 SIGNOR-259942 0.425 MAPK3 protein P27361 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Thr30 PSSSEIFtPAHEENV 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264772 0.2 CDS2 protein O95674 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-267020 0.8 HK2 protein P52789 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-266446 0.8 RBX1 protein P62877 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 11295495 t gcesareni The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-106781 0.451 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 0.469 NKX2-5 protein P52952 UNIPROT LYL1 protein P12980 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19608273 f Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors. SIGNOR-253655 0.313 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 0.2 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 0.8 SMURF2 protein Q9HAU4 UNIPROT 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-236090 0.738 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 BTO:0000776 9012831 t gcesareni We now describe a protein, bap-135, that is associated with btk in b cells and is a substrate for phosphorylation by btk.Taken together, these observations suggest that bap-135 may reside downstream of btk in a signaling pathway originating at the bcr. SIGNOR-46060 0.517 AMPK complex SIGNOR-C15 SIGNOR ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 29899443 t Human ACC1 is inactivated by phosphorylation at Ser80, Ser1201 and Ser1216 by AMP-activated protein kinase (AMPK) SIGNOR-267475 0.559 ROR2 protein Q01974 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 23151663 t gcesareni Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase SIGNOR-199588 0.2 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 0.717 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 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 0.26 BMI1 protein P35226 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 19884659 f gcesareni Chromatin immunoprecipitation assays revealed the bmi-1 transcriptionally downregulated expression of the tumor suppressor pten in tumor cells through direct association with the pten locus. SIGNOR-189040 0.55 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256325 0.283 RGS6 protein P49758 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates binding 9606 17609107 t flangone Numb binds to integrin-betas and localizes to clathrin-coated structures SIGNOR-156762 0.2 CARM1 protein Q86X55 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity methylation Arg223 PAPTPNPrASLNHST 9606 BTO:0000725 24332853 t miannu We have found that PRMT4 is highly expressed in HSPCs, where it functions as an inhibitor of myeloid differentiation (Figure 7G). In these cells, PRMT4 methylates RUNX1 at R223, promoting the assembly of a DPF2-containing transcriptional co-repressive complex, and repressing transcription at the miR-223 locus. SIGNOR-261967 0.282 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 0.8 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT up-regulates activity phosphorylation Tyr455 PARSSDSyAVIDLKK 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-250203 0.602 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5 SIGNOR-60471 0.347 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 0.854 BRCA1 protein P38398 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity 9606 BTO:0000356;BTO:0001033 11244506 f The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines. SIGNOR-253974 0.754 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1336 RFMDGSPyAHMFEMS 9606 BTO:0000007 11024032 t Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. SIGNOR-251173 0.768 CHUK protein O15111 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation 9606 BTO:0000093 18490760 t gcesareni Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation SIGNOR-178664 0.296 PTPN11 protein Q06124 UNIPROT PDCD1 protein Q15116 UNIPROT down-regulates activity dephosphorylation 9606 32437509 t miannu Related to the latter notion, we recently showed that SHP2 dephosphorylates PD-1 to disassemble the PD-1:SHP2 complex ( xref ). SIGNOR-277052 0.659 afimoxifene chemical CHEBI:44616 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258594 0.8 MFF protein Q9GZY8 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity relocalization 9606 21149567 t gcesareni Mff functions as an essential factor in mitochondrial recruitment of Drp1. SIGNOR-245957 0.601 HLX protein Q14774 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 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-261623 0.2 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity precursor of 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266496 0.8 amisulpride chemical CHEBI:64045 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-258365 0.8 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 0.2 PKC proteinfamily SIGNOR-PF53 SIGNOR AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser180 TIFASCDsKRTDVTG -1 19761816 t miannu Taken together this data shows that AQP4 in gliomas is the target of PKC phosphorylation, and albeit significantly phosphorylated at rest, phosphorylation can be further enhanced by PKC activation.This data suggests that in gliomas water permeability through AQP4 is under the regulation of PKC via phosphorylation of S180. SIGNOR-276260 0.2 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 0.2 SIGMAR1 protein Q99720 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization stabilization 9606 BTO:0000815 29117944 t Barakat We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells SIGNOR-274974 0.2 LYL1 protein P12980 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 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-253923 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR BIRC2 protein Q13490 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16510124 t miannu Since Fbxo7 is one component of the SCF complex, we tried to determine whether overexpression of Fbxo7 could promote cIAP1 ubiquitination in the hope to reveal functional aspects of the cIAP1–Fbxo7 interaction. cIAP1-Flag was co-expressed with or without Fbxo7 in 293T cells. In conclusion, our results show that overexpression of Fbxo7 promotes the ubiquitination of cIAP1. SIGNOR-271553 0.308 F12 protein P00748 UNIPROT KLKB1 protein P03952 UNIPROT up-regulates activity cleavage Arg390 CTTKTSTrIVGGTNS 9606 BTO:0000131 28966616 t lperfetto FXIIa activates two serine proteinases, factor XI (FXI) and plasma prekallikrein (PK) that drive the coagulation and kallikrein–kinin systems, respectively SIGNOR-263518 0.606 KLF4 protein O43474 UNIPROT SRF protein P11831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni Klf4 antagonizes contractile gene expression through diverse mechanisms including (i) inhibiting the binding of srf-myocd or srf-mrtfs to the carg box by direct association with srf. SIGNOR-174258 0.368 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 0.427 PPP2CA protein P67775 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-248636 0.455 UBE2N protein P61088 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates activity ubiquitination -1 19240029 t miannu We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s. SIGNOR-272737 0.539 MAP1B protein P46821 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000938 10649507 t lperfetto MAP1B is a microtubule-associated phosphoprotein that is particularly highly expressed in developing neurons.  SIGNOR-264844 0.7 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 0.635 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser262 LRIAKTPsPPEEPSP 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126839 0.396 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 0.618 BBC3 protein Q9BXH1 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates binding 9606 15694340 t gcesareni Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133817 0.752 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 0.536 PRKACA protein P17612 UNIPROT CA9 protein Q16790 UNIPROT up-regulates phosphorylation Thr443 RRQHRRGtKGGVSYR 9606 22037869 t llicata Here, we report that thr443 phosphorylation at the intracellular domain of ca ix by protein kinase a (pka) is critical for its activation in hypoxic cells, with the fullest activity of ca ix also requiring dephosphorylation of ser448. SIGNOR-176973 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A5/b1 integrin complex SIGNOR-C163 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-259017 0.366 DOK1 protein Q99704 UNIPROT A4/b7 integrin complex SIGNOR-C187 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-257697 0.324 PLK1 protein P53350 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2439 SFLSGEPsQADVQPL 9606 BTO:0000552 31597699 t miannu As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F). SIGNOR-277490 0.402 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190497 0.8 DHODH protein Q02127 UNIPROT coenzyme Q10 smallmolecule CHEBI:46245 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-267431 0.8 Serdemetan chemical CID:11609586 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193504 0.8 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 0.448 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 0.8 TDGF1 protein P13385 UNIPROT TGFB1 protein P01137 UNIPROT down-regulates activity binding 9606 17030617 t lperfetto Ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI. SIGNOR-150006 0.2 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16371461 t lperfetto Phosphorylated gli3 can bind beta-trcp directly both in vitro and in vivo, resulting in polyubiquitination of gli3 and processing through proteasome activity SIGNOR-143171 0.671 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 0.433 WNT4 protein P56705 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60373 0.312 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276089 0.288 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS1 protein O95835 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15688006 t Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1¬ñ588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. SIGNOR-270217 0.2 (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 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-258464 0.8 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 0.39 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-252493 0.509 RNF8 protein O76064 UNIPROT BLM protein P54132 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001938 23708797 t miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .  SIGNOR-272115 0.337 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219328 0.759 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 0.557 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 0.2 NCBP3 protein Q53F19 UNIPROT mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 26382858 f 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-268362 0.7 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 0.665 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243442 0.834 PROK1 protein P58294 UNIPROT PROKR1 protein Q8TCW9 UNIPROT up-regulates binding 9606 12054613 t gcesareni The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2) SIGNOR-89084 0.412 DCTPP1 protein Q9H773 UNIPROT dCMP 3'-end residue smallmolecule CHEBI:53119 ChEBI up-regulates quantity by expression chemical modification 10116 31377845 t lperfetto Our data indicate that DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing a new player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity SIGNOR-261333 0.8 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys6 kGGKGLGK -1 11585814 t lperfetto During nucleosome assembly in vivo, newly synthesized histone H4 is specifically diacetylated on lysines 5 and 12 within the H4 NH(2)-terminal tail domain. The highly conserved "K5/K12" deposition pattern of acetylation is thought to be generated by the Hat1 histone acetyltransferase, which in vivo is found in the HAT-B complex. SIGNOR-264791 0.2 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 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2A complex SIGNOR-C347 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-264128 0.8 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser292 QLLRRESsVGYRVPA 9606 21209314 t llicata Here, we report the identification of serine 292 in rin1 as an in vivo pkd phosphorylation site. we demonstrate that phosphorylation at serine 292 controls rin1-mediated inhibition of cell migration by modulating the activation of abl kinases. SIGNOR-170877 0.402 IL5RA protein Q01344 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 7602114 t Jak 2 is physically associated with the IL-5b receptor. The binding of IL-5 to its receptor results in tyrosine phosphorylation and activation of Jak 2 tyrosine kinase within 1 to 3 min. SIGNOR-254352 0.602 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 f miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology SIGNOR-263818 0.7 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-200809 0.8 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 0.732 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 0.781 ADORA2B protein P29275 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-256910 0.524 Dinaciclib chemical CID:46926350 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191325 0.8 STK26 protein Q9P289 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 t lperfetto Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin. SIGNOR-185563 0.2 USP24 protein Q9UPU5 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000018 27991932 t lperfetto In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels SIGNOR-275606 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SP1 protein P08047 UNIPROT up-regulates binding 9606 10671503 t lperfetto Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1. SIGNOR-216334 0.559 NCSTN protein Q92542 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 t lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) SIGNOR-209711 0.964 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 0.7 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 0.68 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 f gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) ² plays an essential role. SIGNOR-250562 0.7 ROCK2 protein O75116 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 14701738 f 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-261722 0.7 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 0.411 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 12185584 t lperfetto Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies. SIGNOR-91542 0.624 DAMPS stimulus SIGNOR-ST18 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267854 0.7 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 0.2 PTPRC protein P08575 UNIPROT SKAP1 protein Q86WV1 UNIPROT up-regulates activity dephosphorylation Tyr232 EEEKEETyDDIDGFD 9606 BTO:0000661 11909961 t Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling. SIGNOR-248360 0.361 MTMR1 protein Q13613 UNIPROT 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-) smallmolecule CHEBI:57923 ChEBI down-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269804 0.8 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 0.766 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 0.381 NDUFA13 protein Q9P0J0 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added SIGNOR-262153 0.794 RUNX2 protein Q13950 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15564063 f miannu Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. SIGNOR-255078 0.471 FOXA1 protein P55317 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-142940 0.321 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1373652 t gcesareni The question of whether protein tyrosine phosphatases (ptpases) dephosphorylate a multiply phosphorylated peptide in a random or ordered manner was investigated using the synthetic triphosphotyrosyl peptide trdiy(p)etdy(p)y(p)rk, corresponding to the major sites of autophosphorylation of the insulin receptor, as a substrate for four purified ptpases. SIGNOR-18018 0.622 KDM6B protein O15054 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-265361 0.2 RPL39L protein Q96EH5 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-262491 0.728 ALK protein Q9UM73 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates activity phosphorylation Tyr1278 FGMARDIyRASYYRK -1 15938644 t llicata ALK SelectiVely Phosphorylates the First Tyrosine in Its A-Loop Peptide. SIGNOR-250575 0.2 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 BTO:0000007 10764727 t gcesareni The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins. SIGNOR-76832 0.836 LRP5 protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 11336703 t lperfetto Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes SIGNOR-227930 0.684 PPP1CA protein P62136 UNIPROT PFN1 protein P07737 UNIPROT up-regulates dephosphorylation Ser138 MASHLRRsQY 9606 22479341 t lperfetto Knockdown of the catalytic subunit of pp1 (pp1c_), but not pp2a (pp2ac_), increased ps137-pfn1 levels. Pp1c_ binds pfn1 in cultured cells, and this interaction was increased by a phosphomimetic mutation of pfn1 at ser-137 (s137d). Together, these data define pp1 as the principal phosphatase for ser-137 of pfn1 SIGNOR-196816 0.247 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 0.858 GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21853041 f miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. SIGNOR-256062 0.443 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 0.879 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser11 KRIAKRRsPPADAIP -1 15014043 t miannu Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. SIGNOR-262702 0.504 RPEL1 protein Q2QD12 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-267069 0.8 EFNA5 protein P52803 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t gcesareni Members of the epha subfamily of receptor tyrosine kinases and their ephrin-a ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum. SIGNOR-52467 0.922 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138908 0.341 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 0.2 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-70465 0.853 RTKs proteinfamily SIGNOR-PF38 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR 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-259032 0.2 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr811 RPSFSTIyQELQSIR 9606 8663427 t llicata Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713. SIGNOR-42659 0.2 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190988 0.8 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1109 FDEIELAyRRRPPRS -1 11024032 t Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. SIGNOR-251171 0.768 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 0.2 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 0.7 MAP2K1 protein Q02750 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12270934 f lperfetto We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process. SIGNOR-235325 0.263 PIP3 smallmolecule CHEBI:16618 ChEBI WIPI1 protein Q5MNZ9 UNIPROT up-regulates chemical activation 9606 22082875 t gcesareni We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes. SIGNOR-177169 0.8 RPS6KA5 protein O75582 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 t lperfetto In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo. SIGNOR-249296 0.383 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 t lperfetto Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase. SIGNOR-126753 0.843 PIK-90 chemical CID:6857685 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206232 0.8 CYP24A1 protein Q07973 UNIPROT calcitetrol smallmolecule CHEBI:47799 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-270571 0.8 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 0.711 ZNF140 protein P52738 UNIPROT FCGR3B protein O75015 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0002269 11470777 t Luana Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription. SIGNOR-266214 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Asn) smallmolecule CHEBI:29172 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-269482 0.8 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser191 YSFYSTCsGQKAIKK -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-273487 0.267 CCAR2 protein Q8N163 UNIPROT SUV39H1 protein O43463 UNIPROT down-regulates activity binding 26158765 t lperfetto Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation. SIGNOR-267664 0.346 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0000725 23645839 f apalma Prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255685 0.8 SRC protein P12931 UNIPROT HCN4 protein Q9Y3Q4 UNIPROT up-regulates phosphorylation Tyr531 RRQYQEKyKQVEQYM 9606 17977941 t fspada These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531. SIGNOR-158707 0.371 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 0.2 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 0.341 AKT3 protein Q9Y243 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 BTO:0000150 20231902 t inferred from 70% of family members gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-269941 0.271 ARNT protein P27540 UNIPROT FOS protein P01100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21544813 f lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC SIGNOR-253696 0.287 ADCY6 protein O43306 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265001 0.8 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 0.759 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-60115 0.779 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 0.8 Ub:RING_E3 complex SIGNOR-C519 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-271383 0.7 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser11 DFGFFSSsESGAPEA -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-250842 0.309 KANSL2 protein Q9H9L4 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267163 0.668 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 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252825 0.911 TLN1 protein Q9Y490 UNIPROT A6/b1 integrin complex SIGNOR-C164 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-257613 0.621 WWP2 protein O00308 UNIPROT SLC11A2 protein P49281 UNIPROT down-regulates quantity ubiquitination 10029 BTO:0000246 18776082 t lperfetto Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2|This promotes DMT1 ubiquitination and degradation by WWP2. SIGNOR-268852 0.299 lovastatin chemical CHEBI:40303 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1597859 t miannu A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). SIGNOR-258351 0.8 PTGER3 protein P43115 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-256859 0.457 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 0.2 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 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-121601 0.364 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 0.263 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 9889196 t lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. SIGNOR-63891 0.942 TLN1 protein Q9Y490 UNIPROT AX/b2 integrin complex SIGNOR-C171 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-257621 0.486 UBE4B protein O95155 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 15611659 t miannu We further demonstrate that Ufd2 directly and efficiently ubiquitylates securin in vitro and is required for securin polyubiquitylation in vivo. This is the first description of a physiologic substrate for Ufd2, establishing this E4 enzyme as an important regulator of chromosome condensation and separation during mitosis in human cells.  SIGNOR-271523 0.2 SETDB2 protein Q96T68 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 t miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. SIGNOR-263894 0.2 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 0.76 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 0.572 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 0.8 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.722 FOXE1 protein O00358 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21177256 f miannu The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. SIGNOR-254174 0.349 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates activity phosphorylation Ser172 SSSEEMEsQLQERVE 9606 BTO:0000007 21362549 t miannu ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation  SIGNOR-276314 0.522 PLK1 protein P53350 UNIPROT AHR protein P35869 UNIPROT down-regulates activity phosphorylation Ser489 ENNFFNEsMNECRNW -1 37988371 t miannu In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.  SIGNOR-277885 0.251 CAMK2B protein Q13554 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 t gcesareni Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. SIGNOR-59358 0.515 MAPK8IP2 protein Q13387 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 9733513 t gcesareni Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7. SIGNOR-59944 0.678 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 0.4 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 0.2 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 15854902 t lperfetto Rheb binds and regulates the mTOR kinase. SIGNOR-135770 0.95 TGFB1 protein P01137 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity 9606 19114990 f lperfetto First, TGF-beta can rapidly activate PI3K, as indicated by the phosphorylation of its downstream effector Akt SIGNOR-217812 0.274 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 0.49 IFNG protein P01579 UNIPROT S100A10 protein P60903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0002923 12645529 f miannu The effect of interferon (IFN)-gamma on p11 expression was studied in two human epithelial cell lines (BEAS-2B and HeLa). Treatment with IFN-gamma resulted in increased steady-state levels of p11 mRNA and protein expression, with a time-dependent and dose-dependent effect. SIGNOR-255236 0.266 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by destabilization phosphorylation Thr433 DCDFGDLtPLDF -1 10428966 t TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase. SIGNOR-251260 0.434 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI serotonin smallmolecule CHEBI:28790 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 SIGNOR-264186 0.8 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 0.2 TAF9 protein Q16594 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-269582 0.534 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11375397 t lperfetto Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity. SIGNOR-236519 0.76 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89162 0.553 HDLBP protein Q00341 UNIPROT CSF1R protein P07333 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 33941620 t miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. SIGNOR-266696 0.342 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 0.596 EXOSC2 protein Q13868 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261387 0.95 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser381 CIPTAGMsPSRSNTI 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-249459 0.633 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190723 0.8 dothiepin chemical CHEBI:36798 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-258699 0.8 AIP protein O00170 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 21984905 t In this study, 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-253643 0.2 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 0.2 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t gcesareni FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4 SIGNOR-248055 0.606 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 0.346 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 0.307 TP53INP2 protein Q8IXH6 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 19056683 t gcesareni Tp53inp2 is a scaffold protein that recruits lc3 and/or lc3-related proteins to the autophagosome membrane by interacting with the transmembrane protein vmp1 SIGNOR-182614 0.408 MOB1A protein Q9H8S9 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1 SIGNOR-269866 0.941 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 0.2 quetiapine chemical CHEBI:8707 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 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-258535 0.8 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 0.2 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 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-44243 0.625 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 0.8 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE 9606 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-119216 0.2 FOXJ1 protein Q92949 UNIPROT EFHC1 protein Q5JVL4 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-266934 0.356 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 0.311 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275871 0.2 AREL1 protein O15033 UNIPROT MTX2 protein O75431 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 34584540 t lperfetto Therefore, these results implied that AREL1 ubiquitinates and promotes the degradation of MTX2. SIGNOR-267674 0.2 AKT2 protein P31751 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f gcesareni It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-101324 0.639 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 0.83 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 0.354 STMN1 protein P16949 UNIPROT TTL protein Q8NG68 UNIPROT down-regulates binding 9606 23624152 t miannu Stathmin depresses ttl tubulin tyrosination activityin vitro. SIGNOR-193465 0.389 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 0.2 UHMK1 protein Q8TAS1 UNIPROT PAM protein P19021 UNIPROT unknown phosphorylation Ser946 DRLSTEGsDQEKEDD 9606 BTO:0004055 10574929 t lperfetto Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2. B SIGNOR-247009 0.444 MAPK8 protein P45983 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 9030579 t llicata The a/b domain of human ppargamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (s84a) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by erk2 and jnk, and this was markedly reduced in the s84a mutant. Thus, phosphorylation of a mitogen-activated protein kinase site in the a/b region of ppargamma inhibits both ligand-independent and ligand-dependent transactivation functions. SIGNOR-46518 0.527 BAG5 protein Q9UL15 UNIPROT PRKN protein O60260 UNIPROT down-regulates activity binding 9606 BTO:0000007 15603737 t Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity Immunoprecipitation (IP) of GFP-parkin resulted in the coimmunoprecipitation of both Hsp70 and BAG5 or BAG5(DARA) (Figure 4A). Furthermore, IP of GFP-parkin resulted in the coimmunoprecipitation of BAG5 or BAG5 (DARA) in the absence of overexpressed Hsp70. Taken together, these data demonstrate that BAG5 can directly inhibit parkin-mediated autoubiquitinylation independently of Hsp70. SIGNOR-261198 0.2 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr423 NSLNEEWyVSYITRP -1 8702662 t Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro SIGNOR-251381 0.754 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 0.45 KAT2B protein Q92831 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity acetylation 32917954 t SimoneGraziosi NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase SIGNOR-269270 0.469 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 0.479 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 0.8 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 19478061 t Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active SIGNOR-248442 0.517 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 9534 BTO:0004055 15367659 t lperfetto Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. SIGNOR-249270 0.516 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 0.7 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 0.2 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT up-regulates activity phosphorylation Ser220 EPLAVVGsPYWMAPE -1 10207045 t Manara These results suggest that autophosphorylation of Ser-215 is an important step to positively regulate the kinase activity of TESK1. SIGNOR-260825 0.2 AKT1 protein P31749 UNIPROT BTK protein Q06187 UNIPROT down-regulates quantity by destabilization phosphorylation Ser51 FERGRRGsKKGSIDV 9606 BTO:0003289 23754751 t miannu The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.  SIGNOR-276466 0.296 GSK1059615 chemical CHEBI:71955 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252667 0.8 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 0.381 FZD2 protein Q14332 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-258965 0.667 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 26721223 f Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. SIGNOR-255493 0.7 PSPC1 protein Q8WXF1 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 BTO:0000669 23308148 t miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. SIGNOR-223973 0.406 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 0.8 CCR4-NOT complex complex SIGNOR-C439 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI down-regulates quantity by destabilization chemical modification 9606 31320642 t lperfetto CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. |The poly(A) tails at 3′ ends of eukaryotic mRNAs are crucial for their cytoplasmic stability and to enhance the initiation of translation. Newly synthesized metazoan mRNAs possess long poly(A) tails1, and following export to the cytoplasm the tails are reported to be ~60–80 nucleotides on average at steady state2. Poly(A) tails are also important for translational efficiency at the embryonic stage2 and the length of the poly(A) tail was reported to be correlated with translational efficiency3. The multisubunit CCR4-NOT complex is principally responsible for efficient processive shortening of poly(A) tails, or deadenylation, in addition to other function SIGNOR-268312 0.8 LEF1 protein Q9UJU2 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 16936075 f The other members of the Lef1 HMGB1 protein super-family, Tcf1 and Tcf3, were also expressed in the PSM and the newly formed somites, although at a lower level than was Lef1. gcesareni Furthermore, we show that direct activation is mediated by binding of the tcf-lef/ - catenin complex to the myf5 epaxial enhancer and to a newly identified element upstream of this enhancer. SIGNOR-149170 0.252 PKC proteinfamily SIGNOR-PF53 SIGNOR GNE protein Q9Y223 UNIPROT up-regulates activity phosphorylation 10116 BTO:0000759 10745088 t lperfetto Protein kinase C phosphorylates and regulates UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase|Furthermore, PKC phosphorylates UDP-GlcNAc 2-epimerase and this phosphorylation results in an upregulation of the UDP-GlcNAc 2-epimerase enzyme activity. SIGNOR-266072 0.2 AURKB protein Q96GD4 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser278 QKVAERRsSPLLRRK 9606 22865920 t lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions SIGNOR-198650 0.258 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 0.8 RPS6KA5 protein O75582 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 12628924 t lperfetto Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276. SIGNOR-217424 0.621 CSNK2A1 protein P68400 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates phosphorylation Thr494 TEAVQDPtKVEAHVR 9606 17932117 t lperfetto Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype. SIGNOR-158319 0.2 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 0.624 HIF1A protein Q16665 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271564 0.259 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 0.9 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 0.2 SF3B1 protein O75533 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-268403 0.939 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 10980595 t inferred from 70% family members 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-270014 0.2 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE 9534 BTO:0000298 8557118 t lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-248939 0.365 STOML2 protein Q9UJZ1 UNIPROT SDHD protein O14521 UNIPROT up-regulates activity 9606 20359165 f Giorgia We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain. SIGNOR-260383 0.21 AICA-Ribotide chemical CID:16760280 PUBCHEM PRKAA2 protein P54646 UNIPROT up-regulates chemical activation 9606 BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 19491292 t gcesareni Aicar-induced ampk phosphorylation inhibits cell cycle transition, reducing differentiation of myoblasts into myotubes, through pgc-1alpha-foxo3a-p21. SIGNOR-186055 0.8 P2RY10 protein O00398 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257287 0.2 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability SIGNOR-77705 0.367 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-29923 0.601 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 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-133845 0.2 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 0.484 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 0.2 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 0.454 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 0.27 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000038 17875931 t irozzo We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein. SIGNOR-256138 0.592 OGDC complex SIGNOR-C397 SIGNOR NADH smallmolecule CHEBI:16908 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-266259 0.8 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 0.425 MET protein P08581 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr56 DRPQEVSyTDTKVIG 9606 BTO:0000972 30711629 t miannu  MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells.  SIGNOR-277428 0.308 PRKAA1 protein Q13131 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 SIGNOR-C15 11971957 t gcesareni Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka. SIGNOR-86133 0.342 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys121 GESVYGEkRVSISEG 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275895 0.271 AKT proteinfamily SIGNOR-PF24 SIGNOR NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t lperfetto Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype. SIGNOR-244318 0.2 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190332 0.8 FGR protein P09769 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 12387730 t gcesareni Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr. SIGNOR-94405 0.552 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 0.8 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys205 RDLINLAkKRTNIIP 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275896 0.27 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 0.492 UPF2 protein Q9HAU5 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-265238 0.973 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 12917434 t lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1 SIGNOR-117852 0.71 MUSK protein O15146 UNIPROT WNT11 protein O96014 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like ror, musk has an extracellular region with homolgogy to the frizzled crd, binding of which by wnt11 stimulates a pcp-like pathway during neuromuscular development SIGNOR-199518 0.456 MAML3 protein Q96JK9 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates binding 9606 12370315 t esanto Whereas maml1 and maml2 functioned efficiently as coactivators with each of the notch receptors to transactivate a notch target hes1 promoter construct, maml3 functioned more efficiently with icn4 than with other forms of icn. SIGNOR-94103 0.867 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 0.747 PRKD3 protein O94806 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser498 RPLSRTQsSPLPQSP 18692497 t lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275928 0.265 MRPS17 protein Q9Y2R5 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 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-261453 0.2 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275947 0.2 JAK2 protein O60674 UNIPROT BRD4 protein O60885 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr97 VKLNLPDyYKIIKTP 9606 BTO:0002181 34290255 t miannu JAK2 induces tyrosine phosphorylation of BRD4 at Y97/Y98, resulting in BRD4 stabilization.  SIGNOR-277313 0.324 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 0.709 erlotinib hydrochloride chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191502 0.8 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275955 0.393 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248377 0.614 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 0.2 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 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-199384 0.584 MMP9 protein P14780 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-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation. SIGNOR-74461 0.592 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 INTS4 protein Q96HW7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity binding 9606 16239144 t miannu The Integrator Complex Can Directly Associate with the C-Terminal Domain of RNA Polymerase II Largest Subunit SIGNOR-261185 0.541 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 0.56 Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 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-270750 0.7 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 0.46 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 0.2 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 0.306 COP1 protein Q8NHY2 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 t lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes SIGNOR-154514 0.2 KANSL3 protein Q9P2N6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 26243146 f miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. SIGNOR-267169 0.7 CDH4 protein P55283 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-265866 0.527 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr797 ERPGGTPtPVIAYSK -1 19448668 t miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. SIGNOR-262881 0.379 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 0.2 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 0.589 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 0.765 PBX1 protein P40424 UNIPROT CDH1 protein P12830 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-267241 0.267 CDK5 protein Q00535 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni 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. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity. SIGNOR-92269 0.395 PLK3 protein Q9H4B4 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser73 VSTQELYsIPEDQEP -1 16481012 t miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  SIGNOR-276051 0.66 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 0.683 PRKCA protein P17252 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation Ser388 VPQPLVDsYRQQQQL 9606 19158275 t miannu Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.  SIGNOR-276235 0.2 NDUFA2 protein O43678 UNIPROT NADH-ubiquinone oxidoreductase-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 0.862 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 0.642 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 0.589 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 18632848 t amattioni The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. SIGNOR-179469 0.835 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation -1 17525164 t miannu AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2.  SIGNOR-276065 0.902 AKT1 protein P31749 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t llicata 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-116587 0.673 PPP2CA protein P67775 UNIPROT MAP2K2 protein P36507 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-166652 0.493 CEBPA protein P49715 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-254042 0.259 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-75898 0.378 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 0.581 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250806 0.345 MAPK11 protein Q15759 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-251833 0.2 rauwolscine chemical CHEBI:48562 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 t miannu These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor SIGNOR-258690 0.8 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 0.25 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 0.371 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191436 0.8 F2R protein P25116 UNIPROT RAB3A protein P20336 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-254845 0.2 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 0.839 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 0.395 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 0.531 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-202113 0.366 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 0.2 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 0.2 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 0.26 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2054 LLKNGANkDMQNNRE 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-156919 0.414 NPY protein P01303 UNIPROT Food intake phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 10195157 f miannu Neuropeptide Y (NPY) stimulates food intake and promotes weight gain, whereas melanocortins have the opposite effect. SIGNOR-263505 0.7 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 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR GABRB2 protein P47870 UNIPROT up-regulates activity phosphorylation Ser472 SRLRRRAsQLKITIP 9606 BTO:0000007 12818177 t miannu Here we report that Akt phosphorylates, both in vitro and in vivo, the type A gamma-aminobutyric acid receptor (GABA(A)R), the principal receptor mediating fast inhibitory synaptic transmission in the mammalian brain. Akt-mediated phosphorylation increases the number of GABA(A)Rs on the plasma membrane surface, thereby increasing the receptor-mediated synaptic transmission in neurons. These results identify the GABA(A)R as a novel substrate of Akt, thereby linking Akt to the regulation of synaptic strength. SIGNOR-262619 0.2 CDK1 protein P06493 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr1161 FFNPVCAtPNSKILK 9606 29771379 t miannu Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. SIGNOR-265994 0.489 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7230 KPSSRAAsPTRSSSS 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-264428 0.435 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 0.8 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 0.636 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 0.2 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252965 0.714 MAPK1 protein P28482 UNIPROT PLA2G4A protein P47712 UNIPROT unknown phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000567 9468497 t llicata The inhibitor of the 38-kda stress-activated protein kinase (p38(mapk)), sb 203580, reduced phosphorylation of both ser-505 and ser-727 by 50 and 60%, respectively, in thrombin-stimulated platelets. SIGNOR-55706 0.656 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 0.402 DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 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-255809 0.378 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 0.7 CDC7 protein O00311 UNIPROT MCM4 protein P33991 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni Activation of the eukaryotic replicative dna helicase, the mcm2-7 complex, requires phosphorylation by cdc7/dbf4 (dbf4-dependent kinase or ddk), which, in turn, depends on prior phosphorylation of mcm2-7 by an unknown kinase (or kinases).we propose that the resulting mec1 modification of mcm4 and mcm6 further activates ddk phosphorylation of mcm2-7 ( fig. 7aii ). SIGNOR-169453 0.958 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr33 KFKNEDLtDELSLNK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276205 0.2 PCK1 protein P35558 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 30193097 t miannu √Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ† SIGNOR-266588 0.8 ZNF224 protein Q9NZL3 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 17900823 f inferred from family member miannu We previously reported that ZNF224, a novel Kr√ºppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. SIGNOR-270227 0.489 ELF4 protein Q99607 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR form complex binding 9606 BTO:0001271 10207087 t miannu We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function SIGNOR-66960 0.351 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 0.49 NFYC protein Q13952 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-255211 0.2 ABL1 protein P00519 UNIPROT MUC1 protein P15941 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr1243 NGGSSLSyTNPAVAA 9606 16888623 t Manara The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site.  SIGNOR-260830 0.455 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 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-262983 0.2 TDRD3 protein Q9H7E2 UNIPROT SNRPN protein P63162 UNIPROT unknown binding -1 15955813 t miannu the TDRD3 GST-Tudor protein interacted strongly with methylated SmB/B′ and SmD but not with SmE. These results suggest that the Tudor domains of SMN and SPF30 likely interact with assembled snRNPs, whereas the Tudor domain of TDRD3 might bind unassembled methylated Sm proteins. SIGNOR-253518 0.2 IFNA1 protein P01562 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-260334 0.633 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser355 EADLPEPsEKQPAAA -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-275436 0.707 dovitinib; bis(lactic acid) chemical CID:56973714 PUBCHEM KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191421 0.8 FAM20C protein Q8IXL6 UNIPROT FGF23 protein Q9GZV9 UNIPROT down-regulates activity phosphorylation Ser180 IPRRHTRsAEDDSER 9606 24706917 t Manara Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) | Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation.  SIGNOR-260925 0.64 COL1A2 protein P08123 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 11007770 f gcesareni The present study was designed to further characterize tgfbeta up-regulation of col1a2 and more generally, to increase our understanding of the tgfbeta signaling pathway that controls ecm accumulation. SIGNOR-82405 0.7 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity deacetylation Lys38 PSTGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275884 0.2 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 0.7 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEY2 protein Q9UBP5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12548545 f gcesareni SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. SIGNOR-254338 0.2 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser980 VHAPRRCsDGGAHGY 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75359 0.468 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 0.766 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 14965271 t lperfetto Fas (CD95) is activated by its natural ligand FasL SIGNOR-216292 0.903 PRKAA2 protein P54646 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C15 20647423 t gcesareni Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions. SIGNOR-166905 0.2 EPS15 protein P42566 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity binding 10029 BTO:0002988 15383614 t gcesareni We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role SIGNOR-243278 0.755 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 0.441 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr265 KDPKRRMtIAQSLEH 9606 15611134 t gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. SIGNOR-132467 0.2 NDUFA9 protein Q16795 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5) SIGNOR-262160 0.831 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation -1 15133517 t inferred from 70% family members 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‚Äì356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. SIGNOR-270193 0.2 CDK7 protein P50613 UNIPROT 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-116582 0.546 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 0.412 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.912 8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one chemical CHEBI:91361 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194865 0.8 MAOA protein P21397 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264003 0.8 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 0.2 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 0.56 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 0.915 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9395068 t miannu We have previously shown that terfenadine can inhibit both Kv1.5 and HERG with its effects on HERG being approximately 10‐fold more potent SIGNOR-258673 0.8 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-101282 0.459 MAP3K8 protein P41279 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000776; BTO:0000801 16484370 f Mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands SIGNOR-256078 0.356 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3. SIGNOR-270015 0.2 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 0.368 MAPKAPK2 protein P49137 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates activity phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 32409685 t miannu MK2 mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.|OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation. SIGNOR-279542 0.2 HRAS protein P01112 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-175192 0.662 ADK protein P55263 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI down-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267838 0.8 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 0.421 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 0.603 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 0.307 cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity precursor of 9606 9634533 t miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. SIGNOR-267250 0.8 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser384 RLLAALEvASAAMAK 9606 20643644 t Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. SIGNOR-260795 0.2 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Thr88 PKTYVDLtNEETTDS 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). SIGNOR-262611 0.28 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Ser39 ELERVNLsAAQTLRA 9606 19370760 t llicata Stk25 phosphorylates ccm3 at serine 39 and threonine 43 SIGNOR-185388 0.765 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268074 0.8 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 0.8 nitric oxide smallmolecule CHEBI:16480 ChEBI M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 24669294 f apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines SIGNOR-255556 0.7 FGFR3 protein P22607 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0000527 22891331 t llicata Fgfrs phosphorylate pten at tyrosine 240 SIGNOR-191797 0.425 KCNB2 protein Q92953 UNIPROT VAPA protein Q9P0L0 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 t lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. SIGNOR-262124 0.2 ANKLE2 protein Q86XL3 UNIPROT VRK1 protein Q99986 UNIPROT down-regulates 9606 22770216 f miannu Lem4 inhibits the activity of baf's kinase vrk-1 during mitotic exit SIGNOR-198103 0.798 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser832 GISPYFSsRRSSEAS 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-249589 0.562 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX10 protein P56693 UNIPROT down-regulates activity phosphorylation Thr240 GQSHGPPtPPTTPKT 9606 BTO:0002806 29295999 t miannu Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity.ERK2 directly phosphorylates SOX10 at T240 and T244. SIGNOR-277821 0.2 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 26083061 t lperfetto Mitochondrial aconitase and succinate dehydrogenase were among the earliest mammalian Fe-S proteins identified.|The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters SIGNOR-262132 0.8 PPARG protein P37231 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression 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-249555 0.616 mTORC1 complex SIGNOR-C3 SIGNOR Lysosome fusion phenotype SIGNOR-PH231 SIGNOR down-regulates activity 9606 39000072 f miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. SIGNOR-277786 0.7 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 0.851 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 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-165799 0.712 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 0.2 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201302 0.636 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 0.666 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K10 protein Q02779 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks. SIGNOR-97003 0.355 LYN protein P07948 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-249383 0.62 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity precursor of 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267544 0.8 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 0.298 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr258 DMKETKYtVDKRFGM 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-85777 0.2 PTPN11 protein Q06124 UNIPROT IRF8 protein Q02556 UNIPROT down-regulates activity dephosphorylation 9606 27769062 t miannu We found that Bcr-abl-induced, Shp2 dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor. SIGNOR-277173 0.353 IL10 protein P22301 UNIPROT SCN10A protein Q9Y5Y9 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-253503 0.263 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Val) smallmolecule CHEBI:29183 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-269500 0.8 serotonin smallmolecule CHEBI:28790 ChEBI HTR4 protein Q13639 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264294 0.8 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser784 GVPFRRPsTFGIPRL 9606 BTO:0000671 12082086 t lperfetto G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells SIGNOR-89853 0.569 FYN protein P06241 UNIPROT DLG2 protein Q15700 UNIPROT up-regulates activity phosphorylation Tyr348 TRPPEPVySTVNKLC -1 13129934 t miannu Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site. In COS7 cells, exogenously expressed PSD-93 was phosphorylated, dependent on its membrane localization. In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate. SIGNOR-262874 0.367 MAPK14 protein Q16539 UNIPROT CFLAR protein O15519 UNIPROT up-regulates phosphorylation 9606 19597496 t There are three isoforms of cellular FLIP (c-FLIP): FLIPL, FLIPS and FLIPR gcesareni Here we demonstrate that m. tuberculosis?induced Tnf triggered reactive oxygen species?dependent Activation of ask1 and the tyrosine kinase c-abl (a000161) in mouse macrophages and that flips was phosphorylated on tyr211 and ser4 by c-abl and p38, respectively. SIGNOR-187001 0.373 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr472 EPIQEANyVPMTPGT 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-236412 0.76 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Thr232 YSSNSGPtRREDKFM 9606 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-134855 0.656 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 0.962 FYN protein P06241 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr133 LIIEDPYyGNDSDFE 9534 BTO:0004055 9038134 t We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP. SIGNOR-251150 0.382 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 0.26 TNFRSF17 protein Q02223 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79495 0.2 PSMD2 protein Q13200 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-263344 0.893 FLNA protein P21333 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity 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-258973 0.509 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244307 0.2 MED23 protein Q9ULK4 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-266665 0.739 ZM 336372 chemical CID:5730 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207911 0.8 RELA protein Q04206 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates binding 9606 15988006 t gcesareni P65 and histone deacetylases 4 cooperate to inhibit the ability of mef2 factors to induce the klf2 promoter SIGNOR-138368 0.316 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser649 VPPSPSLsRHSSPHQ 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251240 0.686 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TSPYL2 protein Q9H2G4 UNIPROT up-regulates activity phosphorylation Ser20 RRLSSSEsPQRDPPP 9606 BTO:0000567 11395479 t llicata We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo.  SIGNOR-250752 0.338 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser27 TASRPSSsRSYVTTS -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248879 0.284 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18423396 f fspada Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation. SIGNOR-178269 0.85 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 0.2 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1 protein O95835 UNIPROT up-regulates 9606 23075495 f gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-199196 0.8 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256036 0.8 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR up-regulates activity phosphorylation 9606 8893010 t ggiuliani Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta. SIGNOR-255778 0.713 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 0.7 TAL1 protein P17542 UNIPROT TSG101 protein Q99816 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17229889 t miannu These data suggest that Tal mediates polyubiquitylation of the lysine residues in the VPS28-binding region of TSG101, leading to subsequent degradation of TSG101. SIGNOR-271636 0.2 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 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-157300 0.642 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 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-267503 0.8 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 31340499 f Luana AP-1 Transcription Factors as Regulators of Immune Responses in Cancer SIGNOR-260766 0.7 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-267016 0.8 FLT3 protein P36888 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity 9606 BTO:0002144 28194038 f inferred from family member FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity SIGNOR-270268 0.264 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 14536078 t gcesareni Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380 SIGNOR-118559 0.445 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 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-177255 0.624 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 0.2 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 0.8 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 0.322 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10608806 t lperfetto In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage. SIGNOR-73432 0.856 NR1I3 protein Q14994 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19702527 f miannu Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. SIGNOR-254863 0.47 IQSEC2 protein Q5JU85 UNIPROT GRIA4 protein P48058 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-264915 0.2 IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 f miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 0.7 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 0.343 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 0.51 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FGF1 protein P05230 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-259166 0.8 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 0.2 TRIP12 protein Q14669 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates activity ubiquitination 9606 BTO:0001938 22884692 t miannu Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. SIGNOR-266783 0.465 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 0.2 PRKCD protein Q05655 UNIPROT BAG3 protein O95817 UNIPROT up-regulates phosphorylation Ser187 SSSSSSAsLPSSGRS 9606 23108398 t lperfetto Pkc_-mediated phosphorylation of bag3 at ser187 site induces epithelial-mesenchymal transition and enhances invasiveness in thyroid cancer fro cells. we showed that bag3 was implicated in epithelial-mesenchymal transition (emt) procedure, and phosphorylation state at ser187 site had a critical role in emt regulation by bag3. SIGNOR-199316 0.251 MAPK1 protein P28482 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser160 GVTKAISsPTVSRLT -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. SIGNOR-262928 0.354 MAPK3 protein P27361 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-182782 0.265 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263431 0.798 MTX2 protein O75431 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-267682 0.739 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 19561641 t gcesareni Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e SIGNOR-186418 0.955 CSNK2A1 protein P68400 UNIPROT OTUD5 protein Q96G74 UNIPROT up-regulates activity phosphorylation Ser177 EVGAGYNsEDEYEAA -1 22245969 t miannu Here we show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. Treatment with CK2 could activate DUBA purified from E. coli, and this activity was associated with a species monophosphorylated at Ser177 (Fig. 1d). SIGNOR-265872 0.2 CHEK1 protein O14757 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity phosphorylation Ser331 KSKGRASsSGNQESS 9606 BTO:0005035 19861535 t lperfetto In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage-inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2.|In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1, SIGNOR-263252 0.585 DNMT1 protein P26358 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000775 32905139 t Gianni Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35) SIGNOR-269053 0.488 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr69 ERQLNGTyAIAGGKA 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251396 0.619 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 0.272 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 0.2 KDM6B protein O15054 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 22025054 t lperfetto JMJD3 seems to function by controlling expression of the transcription factor IRF4, which in turn is required for M2 polarization of macrophages in vitro and in vivo. Although this pathway is strongly supported by genetic. SIGNOR-249540 0.422 PRKCB protein P05771 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-89193 0.565 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 0.645 FASN protein P49327 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 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-267212 0.8 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 0.7 PRKD1 protein Q15139 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000661 1370476 t lperfetto Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells. SIGNOR-248846 0.404 PRKAA1 protein Q13131 UNIPROT UCP3 protein P55916 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-156831 0.329 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 0.281 PCCA protein P05165 UNIPROT PCC complex SIGNOR-C414 SIGNOR form complex binding 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267182 0.891 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 0.582 zotepine chemical CHEBI:32316 ChEBI DRD4 protein P21917 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258555 0.8 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 8157000 t gcesareni To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. SIGNOR-262292 0.733 A6/b4 integrin complex SIGNOR-C174 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 9428518 t miannu 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-259033 0.429 CSF2 protein P04141 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates binding 9606 BTO:0000876 BTO:0001103 9680354 t apalma GM-CSF elicits these diverse responses through the GM-CSF receptor (GMR). SIGNOR-255581 0.862 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser259 SQRQRSTsTPNVHMV 9534 BTO:0004055 12801936 t miannu Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259). SIGNOR-250041 0.5 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248328 0.621 ASXL1 protein Q8IXJ9 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates activity binding 9606 16606617 t irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255931 0.283 MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37409 0.7 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 22933625 f apalma Recent findings have shown that IL-10 stimulation of macrophages isolated from skeletal muscles increases the phagocytic activity of macrophages SIGNOR-255443 0.7 TGFBR2 protein P37173 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227528 0.433 NAIP protein Q13075 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256403 0.515 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 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-42960 0.804 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 0.8 MLL2 complex complex SIGNOR-C88 SIGNOR PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198623 0.2 Starvation stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 23000343 f lperfetto Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activationSTARV SIGNOR-209796 0.7 MAPK3 protein P27361 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 12163482 t 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-91143 0.268 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 0.648 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 0.541 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 0.711 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK9 protein P45984 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-111986 0.8 TET1 protein Q8NFU7 UNIPROT PTEN protein P60484 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27121319 t irozzo We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands SIGNOR-259096 0.373 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 0.264 PRKACA protein P17612 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity phosphorylation Ser1598 RNAARRDsVLAASRD -1 12529267 t miannu IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. SIGNOR-249996 0.556 pralatrexate chemical CHEBI:71223 ChEBI TYMS protein P04818 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-259352 0.8 SIRT1 protein Q96EB6 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 19299583 t 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-253722 0.779 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 9029153 t lperfetto Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_ SIGNOR-216698 0.434 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 0.401 DDX5 protein P17844 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 15660129 t miannu The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor SIGNOR-133341 0.702 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates activity phosphorylation Ser185 NRHSPSWsPDGRRRQ 9606 20890132 t miannu In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. Interestingly, the Cdc2/cyclin B1 phosphorylation site Ser185 of Nlp is required for its recognition by PLK1, which enable Nlp depart from centrosomes to allow the establishment of a mitotic scaffold at the onset of mitosis . SIGNOR-259830 0.422 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser426 TQPNINDsLEITKLD 9606 14657031 t lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation SIGNOR-119873 0.704 ZMYM2 protein Q9UBW7 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates activity binding 10090 BTO:0004593 31363497 t miannu In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells. SIGNOR-269802 0.3 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 0.312 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 0.2 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 0.8 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity phosphorylation Ser416 SVDDLANsGQVGTAR 9606 9155023 t lperfetto Tbetarii kinase is regulated intricately by autophosphorylation on at least three serine residues. Phosphorylation of ser416 inhibits receptor function. SIGNOR-48412 0.2 PLK1 protein P53350 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Ser718 QDDPSYRsFHSGGYG 9606 19001871 t lperfetto Ser-718 of beta-catenin was directly phosphorylated by recombinant plk1thus it may be possible that function of the additional phosphorylation site(s) in cooperation with the ser-718 is required for the regulation of _-catenin at m phase SIGNOR-182150 0.399 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 BTO:0000567 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-264484 0.2 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates dephosphorylation 9606 SIGNOR-C110 10644691 t acerquone Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin. SIGNOR-74231 0.435 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 0.556 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser157 GSILSDIsFDKTDES 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-185746 0.638 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 0.425 DYDC1 protein Q8WWB3 UNIPROT Acrosome_assembly phenotype SIGNOR-PH156 SIGNOR up-regulates 9606 19545932 f miannu Knockdown of Dydc1 blocks spermatogenesis and acrosome biogenesis SIGNOR-263881 0.7 MAPK3 protein P27361 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-249447 0.278 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 0.25 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 0.769 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 0.8 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 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-265435 0.2 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 0.794 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 0.765 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 0.758 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 0.8 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 0.2 ERG protein P11308 UNIPROT EPB41L3 protein Q9Y2J2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20860828 f miannu EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. SIGNOR-253918 0.2 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 0.813 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 0.2 PRKCI protein P41743 UNIPROT LLGL2 protein Q6P1M3 UNIPROT up-regulates activity phosphorylation Ser653 LKKSLRQsFRRMRRS 9615 BTO:0000837 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-263180 0.687 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275960 0.2 BMS-265246 chemical CID:5329775 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190434 0.8 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser348 SDLSIASsEEDKLSQ 9606 16837460 t gcesareni Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity. SIGNOR-147883 0.2 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 0.625 TYMS protein P04818 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI down-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268231 0.8 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 16782899 t gcesareni Here we report that fak directly interacts with the hepatocyte growth factor receptor c-met. Phosphorylation of c-met at tyr-1349 and, to a lesser extent, tyr-1356 is required for its interaction with the band 4.1 and ezrin/radixin/moesin homology domain (ferm domain) of fak. met-fak interaction leads to fak activation and subsequent contribution to hepatocyte growth factor-induced cell motility and cell invasion. SIGNOR-147179 0.497 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-265807 0.2 SLA protein Q13239 UNIPROT KIT protein P10721 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0001538 24284075 t miannu In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation which, in turn, is followed by receptor degradation SIGNOR-263143 0.2 KRAS protein P01116 UNIPROT PIK3CA protein P42336 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-175204 0.91 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr681 DIYSTDYyRVGGRTM 9606 9099755 t gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 SIGNOR-47179 0.2 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 23175611 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-199797 0.406 CSNK2A1 protein P68400 UNIPROT SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 t miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. SIGNOR-273633 0.2 MBD5 protein Q9P267 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 20700456 f miannu The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA.Our data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization. SIGNOR-266773 0.7 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 0.2 EFNB1 protein P98172 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. SIGNOR-52517 0.762 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 0.645 PRKCA protein P17252 UNIPROT CFLAR protein O15519 UNIPROT up-regulates quantity by stabilization phosphorylation Ser193 LQAAIQKsLKDPSNN 9606 BTO:0000664 19343040 t miannu  Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins SIGNOR-276147 0.2 Saracatinib chemical CID:10302451 PUBCHEM SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206691 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR CDK18 protein Q07002 UNIPROT up-regulates activity phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 t lperfetto We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  SIGNOR-264559 0.2 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 0.8 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT down-regulates activity binding 10090 BTO:0005787 24627466 t lperfetto Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251715 0.846 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 BTO:0000150 20530684 t lperfetto The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry. SIGNOR-216721 0.595 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 0.2 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 0.346 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 20858476 t gcesareni Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation SIGNOR-167984 0.704 DPYSL2 protein Q16555 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000938 25040932 f lperfetto In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while SIGNOR-264841 0.7 N-[(2S)-1-[[(2S)-1-[[3-[4-(Aminomethyl)piperidine-1-carbonyl]phenyl]methylamino]-3-methyl-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]-1,2-oxazole-5-carboxamide chemical CID:49843508 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition 9606 20873792 t Simone Vumbaca Agonist GB110 (19, EC50 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca2+ release in HT29 human colorectal carcinoma cells. SIGNOR-261125 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25A protein P30304 UNIPROT up-regulates ubiquitination 9606 15340381 t lperfetto Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases. SIGNOR-217178 0.48 UQCR10 protein Q9UDW1 UNIPROT CoQ-cytochrome c reductase-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 0.928 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.878 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 0.343 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 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-271369 0.477 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 0.8 MEN1 protein O00255 UNIPROT MLL-AF4 fusion protein SIGNOR-FP4 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-255868 0.2 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 0.583 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’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b. SIGNOR-267811 0.258 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 0.61 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161678 0.622 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 0.563 very long-chain (R)-3-hydroxyacyl-CoA(4-) smallmolecule CHEBI:85440 ChEBI very long-chain 2,3-trans-enoyl CoA(4-) smallmolecule CHEBI:83728 ChEBI up-regulates quantity precursor of 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-267916 0.8 CIITA protein P33076 UNIPROT HLA-DRB5 protein Q30154 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 f These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. SIGNOR-254013 0.469 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 0.497 FEV protein Q99581 UNIPROT ICAM1 protein P05362 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12761502 f miannu Fev acts as a transcriptional repressor through its dna-binding ets domain and alanine-rich domain. / we show here that fev dramatically represses both basal and ectopically ets-activated transcription driven by the icam-1 promoter, and that the effect is dose dependent. SIGNOR-101246 0.2 regorafenib chemical CHEBI:68647 ChEBI TAP1 protein Q03518 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG3 SIGNOR-259204 0.8 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 0.315 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 0.621 TFEB protein P19484 UNIPROT NDUFA1 protein O15239 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276700 0.2 ATP5F1B protein P06576 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261397 0.2 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 0.8 PTPN11 protein Q06124 UNIPROT ITK protein Q08881 UNIPROT down-regulates activity dephosphorylation 9606 33624224 t miannu Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. SIGNOR-277174 0.324 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 0.749 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 0.8 BMS-740808 chemical CID:6914623 PUBCHEM F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190488 0.8 Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 30205058 t miannu The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. SIGNOR-270793 0.443 adapalene chemical CHEBI:31174 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 30836068 t miannu Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβ in dermal fibroblasts (Kd value 34 nM) and RARγ in the epidermis (Kdvalue 130 nM) SIGNOR-258488 0.8 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 0.296 DNAJC14 protein Q6Y2X3 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 15525720 f lperfetto Mutations in the gene encoding DJ-1 have also been linked to familial Parkinson€™s disease. Other studies have suggested that DJ-1 protects cells from oxidative damage, and mutations in DJ-1 may therefore contribute to in- creased levels of oxidative stress. SIGNOR-249698 0.7 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 0.2 HNRNPA1 protein P09651 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 17371836 f We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alternative splicing SIGNOR-268687 0.7 TOM40 complex complex SIGNOR-C421 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 18423394 f lperfetto The sorting and assembly pathway of outer membrane proteins involves three machineries: the translocase of the outer membrane (TOM complex) the sorting and assembly machinery (SAM complex) and the MDM complex (mitochondrial distribution and morphology). SIGNOR-267688 0.7 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 10116 BTO:0000452 1749429 t lperfetto Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation. SIGNOR-236682 0.5 NKX3-1 protein Q99801 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16697957 t miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. SIGNOR-251547 0.502 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 2861485 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-23958 0.303 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 BTO:0000150 35370244 t miannu Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. SIGNOR-268753 0.8 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 0.708 TFAP2D protein Q7Z6R9 UNIPROT ST8SIA2 protein Q92186 UNIPROT up-regulates quantity by expression transcriptional regulation 9031 24462686 t lperfetto We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2 and the ST8SIA2 promoter.|We show that ST8SIA2 is induced by AP-2δ overexpression in chick retina. We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2δ and the ST8SIA2 promoter. SIGNOR-268992 0.337 EGLN2 protein Q96KS0 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity hydroxylation 9606 24990963 t lperfetto Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.|Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. SIGNOR-261998 0.287 WRC complex complex SIGNOR-C191 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 20332100 f miannu The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex. SIGNOR-253578 0.7 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 0.52 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 0.2 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 0.658 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 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-268662 0.8 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 0.8 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 0.66 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 0.8 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 18758450 t lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-180562 0.2 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 0.2 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 0.265 DCTN6 protein O00399 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9534 BTO:0004055 phosphorylation:Thr186 KTMKGSStPVKN 23455152 t lperfetto Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. SIGNOR-264798 0.374 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser342 ASSVYTRsTGEQEIS 9534 BTO:0000298 10085131 t gcesareni Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. SIGNOR-249675 0.2 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 0.7 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 0.8 celecoxib chemical CHEBI:41423 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190928 0.8 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 0.884 ponatinib chemical CHEBI:78543 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206280 0.8 KDM6B protein O15054 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249564 0.7 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 0.522 SNRPE protein P62304 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-270630 0.835 OPTN protein Q96CV9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0005118 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259876 0.7 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 0.892 SIRT4 protein Q9Y6E7 UNIPROT GLUD2 protein P49448 UNIPROT down-regulates activity glycosylation 9606 16959573 t miannu We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. SIGNOR-268559 0.508 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-58118 0.742 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258458 0.8 SMARCAD1 protein Q9H4L7 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 21549307 t 1 miannu SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin SIGNOR-239835 0.319 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 0.282 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAG3 protein O95817 UNIPROT up-regulates activity phosphorylation Thr285 GSPARSStPLHSPSP 9606 BTO:0000016 27659916 t miannu ERK-dependent phosphorylation of BIS following H2O2 treatment. SIGNOR-274071 0.2 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 0.8 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 0.294 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates binding 9606 24302288 t lperfetto Spectrin is a member of the F-actin-crosslinking protein superfamily. SIGNOR-266030 0.7 2-(Decan-2-ylamino)ethyl 4-aminobenzoate chemical CID:50729 PUBCHEM TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 18258442 t Luana As shown in Table 1 all of the bisanthrapyrazoles inhibited the decatenation activity of human topoisomerase IIα in the low micromolar concentration range SIGNOR-257768 0.8 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-252695 0.768 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 0.307 ATP5PB protein P24539 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261401 0.2 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260886 0.38 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 0.424 HPS6 protein Q86YV9 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 HPS8 SIGNOR-260690 0.773 GADD45A protein P24522 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 SIGNOR-C17 10362260 t gcesareni Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex SIGNOR-68221 0.71 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 0.744 SMC3 protein Q9UQE7 UNIPROT MXD1 protein Q05195 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-241278 0.296 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 0.2 DEPTOR protein Q8TB45 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205600 0.727 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 0.609 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 0.791 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 0.8 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 0.267 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 0.862 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis. SIGNOR-267488 0.7 LAMA2 protein P24043 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255984 0.42 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR 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-216713 0.2 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr472 ICALRHLtSRHQEAE 9606 BTO:0000938 24117889 t lperfetto Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552. SIGNOR-202833 0.289 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 0.833 FOXL2 protein P58012 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19010791 f miannu Foxl2 can directly activate the transcription of sirt1 SIGNOR-182300 0.501 MAPK8 protein P45983 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-89440 0.672 AX/b2 integrin complex SIGNOR-C171 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269020 0.7 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 0.401 A11/b1 integrin complex SIGNOR-C168 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-269017 0.7 ADRB1 protein P08588 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256901 0.392 RAB2A protein P61019 UNIPROT TRIP11 protein Q15643 UNIPROT up-regulates activity binding 9606 BTO:0000567 25473115 t Sara Vesicle-associated Rab2 then mediates attachment to the Rab2 binding site within the central coiled-coil region of GMAP-210, bringing the vesicle into closer proximity to the target membrane. GMAP-210 function in vivo is dependent upon its ability to tether membranes, which is mediated exclusively by the amino-terminal ALPS motif. Binding to Rab2 is also important for GMAP-210 function, although it is dispensable for tethering per se. SIGNOR-261300 0.394 ATG14 protein Q6ZNE5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 10090 BTO:0000944 19270693 t lperfetto Characterization of the new proteins revealed that atg14l enhances vps34 lipid kinase activity and upregulates autophagy, SIGNOR-235448 0.881 SMURF1 protein Q9HCE7 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity ubiquitination 9606 12738770 t lperfetto Smurf1 interacts directly with Cbfa1 and mediates Cbfa1 degradation in a ubiquitin- and proteasome-dependent manner. SIGNOR-236083 0.504 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates deubiquitination 9606 16027725 t gcesareni Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases SIGNOR-138876 0.378 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 0.8 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 0.95 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 0.272 TRIM27 protein P14373 UNIPROT MAPK11 protein Q15759 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-102022 0.2 DNA_damage stimulus SIGNOR-ST1 SIGNOR MLH1/PMS2 complex SIGNOR-C59 SIGNOR up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259062 0.7 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys77 KYWWKNCkMWAIGIT 9606 BTO:0000007 23353890 t miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. SIGNOR-272095 0.328 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser87 PLKQKQPsFSAKKMT 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276381 0.309 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-104807 0.853 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 0.615 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 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Thr73 YGGEKFAtLAELVQY 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276893 0.2 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 0.2 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 0.808 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 0.367 RUBCN protein Q92622 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates binding 9606 19270693 t gcesareni The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34 SIGNOR-184547 0.2 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser93 SSLLSRSsSGYFSFD 9606 BTO:0002181 23912711 t miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  SIGNOR-276247 0.376 PSME2 protein Q9UL46 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 35932807 t lperfetto While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. SIGNOR-275868 0.631 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1787 SPNYSPTsPSYSPTS 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-248746 0.738 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 0.7 PRKCA protein P17252 UNIPROT CASR protein P41180 UNIPROT down-regulates phosphorylation Thr888 FKVAARAtLRRSNVS 9606 21135065 t llicata Casr(t888) is a protein kinase c (pkc) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of casr downstream signaling in vitro, thus, casr(t888) represents a functionally important, inhibitory phosphorylation site that contributes to the control of pth secretion. SIGNOR-170334 0.351 MLST8 protein Q9BVC4 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-205609 0.886 pevonedistat chemical CHEBI:145535 ChEBI UBE2F protein Q969M7 UNIPROT down-regulates quantity chemical inhibition 9606 BTO:0001109 19360080 t Monia MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme; A single dose of MLN4924 resulted in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration of compound SIGNOR-261067 0.8 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 0.2 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 0.862 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 t gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. SIGNOR-167830 0.369 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 0.428 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 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr143 AVSPGTLtPTGVVSG 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276591 0.388 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 17466630 t lperfetto Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-216884 0.419 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 0.798 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 0.2 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 0.343 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 0.311 SPI1 protein P17947 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 BTO:0001413 11483597 t miannu We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222880 0.594 PIN1 protein Q13526 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity isomerization 9606 phosphorylation:Ser416;Ser497;Thr345 GFPSKTDsPSCEYSR;GSLCSVFsPSFVQWE;GADSDVEtPSNFGKY 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-263015 0.2 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 0.67 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 0.307 PDGFRA protein P16234 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 15489898 t gcesareni The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. SIGNOR-247984 0.49 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249396 0.602 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 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-26573 0.542 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 t lperfetto Although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4R and IL-13R1), IL-4 stimulates Jak1 activation. SIGNOR-249529 0.716 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 0.755 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 0.794 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 0.2 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 0.622 TP53 protein P04637 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 t gcesareni Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo. SIGNOR-66956 0.912 CXCL1 protein P09341 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16885213 f gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). SIGNOR-148457 0.2 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 22072711 t The effect has been demonstrated using Q92974-2 gcesareni We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation SIGNOR-177100 0.503 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 0.331 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 0.8 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189168 0.8 ARHGAP30 protein Q7Z6I6 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-260487 0.458 RNF128 protein Q8TEB7 UNIPROT ARHGDIA protein P52565 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-271622 0.266 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 0.31 THR proteinfamily SIGNOR-PF84 SIGNOR RARA protein P10276 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-267779 0.2 COPII vesicle complex SIGNOR-C370 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 9606 30605680 f lperfetto Coat protein complex (COP) II vesicles export newly synthesized secretory proteins from the endoplasmic reticulum (ER) SIGNOR-265297 0.7 YWHAG protein P61981 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-261713 0.266 RAP1GDS1 protein P52306 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc SIGNOR-171347 0.633 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 0.2 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0001412 8692915 t gcesareni Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. SIGNOR-246231 0.414 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser90 QHVRSHSsPASLQLG 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276518 0.258 Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273455 0.7 EEF1A1P5 protein Q5VTE0 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-269553 0.8 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr259 ASVDSSLyNLPRSYS 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236310 0.704 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 0.332 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191136 0.8 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 0.325 SCF-FBW7 complex SIGNOR-C135 SIGNOR TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003492 21254166 t miannu Evidence that Fbw7 acts as the E3-ligase mediating the degradation of topoIIα in HDAC inhibitor-treated PLC5 cells.  SIGNOR-276302 0.343 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr234 AQPEQDEyDIPRHLL 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-246397 0.803 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. SIGNOR-248424 0.2 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 0.7 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 0.2 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr531 NTTGSDNtDTEGS 9606 17936701 t PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. SIGNOR-266900 0.346 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 t gcesareni SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. SIGNOR-75782 0.601 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 0.621 LDHA protein P00338 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24929216 t 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-266918 0.8 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 0.553 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 0.2 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 0.755 PLEKHA7 protein Q6IQ23 UNIPROT TSPAN33 protein Q86UF1 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 t Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. SIGNOR-261250 0.4 PAK2 protein Q13177 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates activity phosphorylation Ser39 RRGRATDsLPGKFED 9606 BTO:0000007 15234964 t miannu Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. When 293T cells are subjected to apoptotic induction by hydrogen peroxide, Mnk1 is phosphorylated at both Thr(22) and Ser(27). These results indicate a role for Pak2 in the down-regulation of translation initiation in apoptosis by phosphorylation of Mnk1. SIGNOR-250221 0.42 ARAF protein P10398 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation 9606 21779497 t gcesareni Active raf phosphorylates mek. SIGNOR-175142 0.754 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 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-176837 0.784 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 0.2 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 0.324 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 0.364 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 0.347 dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity precursor of 9606 BTO:0001363 30943210 t lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone SIGNOR-268659 0.8 XL765 chemical CHEBI:71958 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207878 0.8 GLI1 protein P08151 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-269209 0.457 CBP/p300 complex SIGNOR-C6 SIGNOR EPCAM protein P16422 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11505407 f miannu The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects. SIGNOR-254791 0.254 CDK1 protein P06493 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation Thr376 QVAPRAGtPGFRAPE 9606 10846177 t gcesareni Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. 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. SIGNOR-78311 0.535 TBR1 protein Q16650 UNIPROT FOXP2 protein O15409 UNIPROT up-regulates activity binding 9606 25232744 t miannu We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. SIGNOR-266831 0.556 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 15849194 t Ser112 corresponds to EIRSRHSsYPAGTED lperfetto Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD|Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112. SIGNOR-81165 0.66 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A11 protein P48066 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206990 0.8 NTN4 protein Q9HB63 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268184 0.611 palbociclib chemical CHEBI:85993 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205704 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-244595 0.2 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT down-regulates activity phosphorylation Ser12 RPARKLPsLLLDPTE -1 23954429 t miannu the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters. SIGNOR-266370 0.574 KMT2C protein Q8NEZ4 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30385408 t miannu MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity. We found that MLL3 bound to the enhancer of PD-L1. SIGNOR-260040 0.2 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 0.2 BAK1 protein Q16611 UNIPROT ENDOG protein Q14249 UNIPROT up-regulates 9606 12941691 f gcesareni We show that the mitochondrial outer-membrane permeabilization induced by bax-, tbid- or bax/bak-dependent pro-apoptotic drugs results in the release of cytochrome c, smac/diablo and htra2/omi, but that subsequent caspase activation is required to induce the translocation of endog in addition to aif into the cytosol. SIGNOR-86406 0.292 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 0.405 PRKCB protein P05771 UNIPROT MEP1B protein Q16820 UNIPROT down-regulates quantity phosphorylation Ser687 KKYRERMsSNRPNLT 9534 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-263173 0.2 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 0.8 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 0.348 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser44 LENDFFNsPPRKTVR 9606 15004009 t lperfetto Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia SIGNOR-216682 0.508 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR 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-275680 0.2 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr171 RGTLRKGtLGSKGQK -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273488 0.267 PKI-402 chemical CID:44187953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206259 0.8 RET protein P07949 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates binding 9606 12087092 t amattioni Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret. SIGNOR-90158 0.614 MBD4 protein O95243 UNIPROT CYP27B1 protein O15528 UNIPROT up-regulates quantity by expression transcriptional regulation 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-275682 0.377 MBD4 protein O95243 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 23195996 f lperfetto The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively.  SIGNOR-275683 0.7 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23195996 f lperfetto The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively.  SIGNOR-275684 0.7 UVB radiation stimulus SIGNOR-ST17 SIGNOR DDB1 protein Q16531 UNIPROT up-regulates 24086042 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-275685 0.7 GNAO1 protein P09471 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-256525 0.7 RNF8 protein O76064 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates ubiquitination 9606 20551964 t gcesareni Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist. SIGNOR-166174 0.2 PYY protein P10082 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t esanto Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling. SIGNOR-114749 0.643 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 0.7 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 0.28 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252083 0.2 phosphatidic acid smallmolecule CHEBI:16337 ChEBI MAPK1 protein P28482 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 20231899 t gcesareni In addition, extracellular signal-regulated kinase (erk) is stimulated by ampk-induced pld1 activation through the formation of phosphatidic acid (pa), which is a product of pld SIGNOR-164289 0.8 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 0.403 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267391 0.8 TFAP4 protein Q01664 UNIPROT HDAC1 protein Q13547 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-226590 0.282 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates phosphorylation 9606 16862148 t acerquone Rock phosphorylates filgap, and this phosphorylation stimulates its racgap activity and is a requirement for filgap-mediated bleb formation SIGNOR-148262 0.433 NOTCH1 protein P46531 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19151708 f gcesareni Notch1 directly induces transcription of pin1 SIGNOR-183458 0.384 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Ser307 IRQIRQHsWFRKKHP 9606 BTO:0000887;BTO:0001103;BTO:0001260 19414597 t llicata Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1. SIGNOR-185640 0.321 ITGAX protein P20702 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253193 0.831 ERCC6 protein Q03468 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-275694 0.455 Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR PROC protein P04070 UNIPROT up-regulates activity cleavage 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). SIGNOR-263526 0.721 ACTB protein P60709 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270717 0.494 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 25309941 f Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). SIGNOR-255489 0.7 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 0.2 NLGN3 protein Q9NZ94 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-264157 0.83 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 0.849 Gbeta proteinfamily SIGNOR-PF4 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-270004 0.2 GATA1 protein P15976 UNIPROT NBEAL2 protein Q6ZNJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000132 28082341 f lperfetto In conclusion, we herein show a long-distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression. SIGNOR-261881 0.375 CNTNAP2 protein Q9UHC6 UNIPROT CNTN1 protein Q12860 UNIPROT up-regulates activity relocalization 10090 BTO:0001221 11069942 t Gianni These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr. SIGNOR-269074 0.477 DDX5 protein P17844 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 10090 BTO:0000165 17960593 t miannu P68 (ddx5) interacts with runx2 and regulates osteoblast differentiation. / p68 is a novel co-activator for runx2 SIGNOR-236974 0.453 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 0.2 SOX17 protein Q9H6I2 UNIPROT GLI2 protein P10070 UNIPROT up-regulates 10090 33083751 f SimoneGraziosi Sox17 ablation lowered endogenous Gli2 and Olig2+ cells SIGNOR-269218 0.298 MAML3 protein Q96JK9 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12370315 t gcesareni We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors. SIGNOR-254323 0.884 STK39 protein Q9UEW8 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation 16990453 t lperfetto This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 SIGNOR-264642 0.6 CH5132799 chemical CID:49784945 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190937 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137627 0.2 regorafenib chemical CHEBI:68647 ChEBI MAPK11 protein Q15759 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-259211 0.8 ACAT1 protein P24752 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity acetylation 34289383 t lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) SIGNOR-267633 0.393 NOC3L protein Q8WTT2 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 15564382 f Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation SIGNOR-253060 0.7 alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270808 0.8 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 0.491 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 0.591 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 t gcesareni Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling. SIGNOR-124774 0.643 CTNNB1 protein P35222 UNIPROT SCRIB protein Q14160 UNIPROT up-regulates activity binding 9606 BTO:0000938 21255999 t miannu Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs. SIGNOR-265826 0.434 PLK1 protein P53350 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT down-regulates activity phosphorylation Ser393 VCHDSDEsDTAKAVE 9606 34051063 t miannu 2.11 Plk1 Directly Phosphorylates DNMT3a at S393.|Elevated Plk1 further inhibited DNMT3a via phosphorylation at S393 in mitosis in accord with its mitotic role during cell cycle. SIGNOR-279552 0.269 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TH protein P07101 UNIPROT up-regulates phosphorylation 9606 7901013 t inferred from 70% family members gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 SIGNOR-270055 0.2 PRKCD protein Q05655 UNIPROT ADRA2A protein P08913 UNIPROT up-regulates activity phosphorylation Ser247 RRTRVPPsRRGPDAV 10029 BTO:0000246 11732925 t lperfetto Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling. SIGNOR-249126 0.533 EFL1 protein Q7Z2Z2 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-173492 0.2 NAALAD2 protein Q9Y3Q0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 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-267543 0.8 TFDP1 protein Q14186 UNIPROT RRM1 protein P23921 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253866 0.283 CCL19 protein Q99731 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-268416 0.664 SIRT1 protein Q96EB6 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates deacetylation 9606 BTO:0000938 BTO:0000142 22179316 t miannu Sirt1 deacetylates and activates torc1 SIGNOR-191568 0.281 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates transcriptional regulation 9606 20584981 f fspada Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program.  SIGNOR-210074 0.29 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252686 0.425 ER stress stimulus SIGNOR-ST9 SIGNOR PRNP protein F7VJQ1 UNIPROT up-regulates 9606 BTO:0000007 21478263 f ER stress specifically increases the synthesis of AltPrP from PrP cDNA. SIGNOR-253609 0.7 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 t gcesareni The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158636 0.843 PI-103 chemical CHEBI:90524 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252651 0.8 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 0.89 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-252672 0.782 AMPK complex SIGNOR-C15 SIGNOR HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 21565617 t lperfetto We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases. SIGNOR-216658 0.272 RHOBTB1 protein O94844 UNIPROT PDE5A protein O76074 UNIPROT down-regulates quantity by destabilization 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-272312 0.2 EXOC7 protein Q9UPT5 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12687004 f gcesareni So, the exocyst might have a crucial role in the targeting of the glut4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion SIGNOR-100242 0.548 RNF138 protein Q8WVD3 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16714285 t miannu Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. SIGNOR-271595 0.307 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107680 0.34 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 0.8 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2214 GGRSVPTtPLQVAAP 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181026 0.374 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 t gcesareni We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor SIGNOR-104795 0.754 BCAR1 protein P56945 UNIPROT PKN3 protein Q6P5Z2 UNIPROT up-regulates activity binding 10090 BTO:0002572 30422386 t lperfetto Taken together, the data suggest that p130Cas expression induces PKN3 activation and this activation is independent of p130Cas–PKN3 interaction. SIGNOR-264573 0.2 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser499 VKSRWSGsQQVEQPT 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-97644 0.558 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206385 0.8 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227878 0.895 SRP19 protein P09132 UNIPROT SRP72 protein O76094 UNIPROT up-regulates activity binding -1 30649418 t miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. SIGNOR-261166 0.942 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT RPS2 protein P15880 UNIPROT down-regulates activity binding -1 33188728 t miannu Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. SIGNOR-262508 0.2 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 0.7 KLF4 protein O43474 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0003292 18379898 f miannu The results showed the upregulation of the HSP73 constitutive expression by KLF4 overexpression in both C2C12 cells and murine RAW264.7 macrophages; in response to heat stress, however, few changes were observed in the levels of HSP73 by KLF4 overexpression. SIGNOR-254544 0.2 RABEP1 protein Q15276 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-109352 0.928 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 0.596 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 0.955 OTUB1 protein Q96FW1 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity deubiquitination 19383985 t lperfetto OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells. SIGNOR-276529 0.546 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 15988018 t lperfetto In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif. SIGNOR-138432 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH2 protein P19022 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-265842 0.8 CDK1 protein P06493 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 20169205 t llicata Cdc2 is the raptor ser696, thr706 kinase SIGNOR-163849 0.385 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 22492984 t lperfetto Bim, and puma bind with high affinity to all pro-survival proteins SIGNOR-196935 0.832 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192771 0.8 methionine smallmolecule CHEBI:16811 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264750 0.7 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 0.8 TRAF3 protein Q13114 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16306937 f miannu TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. SIGNOR-256077 0.329 perfluorononanoic acid chemical CHEBI:38397 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-268769 0.8 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 0.7 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 0.781 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 0.386 orotate smallmolecule CHEBI:30839 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-267434 0.8 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 10090 BTO:0000165 17151142 f lperfetto These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38. SIGNOR-235370 0.371 dexamethasone chemical CHEBI:41879 ChEBI CEBPD protein P49716 UNIPROT up-regulates quantity by expression 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-43254 0.8 HDAC1 protein Q13547 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 BTO:0000887 11684023 t gcesareni Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression. SIGNOR-111243 0.547 GOPC protein Q9HD26 UNIPROT ADRB1 protein P08588 UNIPROT down-regulates relocalization 9606 15358775 t miannu Overexpression of cal reduces surface expression of beta1ar. Interaction with cal promotes retention of beta1ar within the cell SIGNOR-128791 0.342 SLC25A13 protein Q9UJS0 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265155 0.8 AMPK complex SIGNOR-C15 SIGNOR AMOTL1 protein Q8IY63 UNIPROT up-regulates quantity by stabilization phosphorylation Ser793 SSLRPARsVPSIAAA 9606 BTO:0000007 25373897 t miannu we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. SIGNOR-263105 0.2 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 0.73 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 0.328 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 16439210 t gcesareni We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity. SIGNOR-142949 0.783 USF1 protein P22415 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19389701 f gcesareni Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes SIGNOR-185575 0.247 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-275399 0.2 PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-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‚Äù SIGNOR-267190 0.8 HSPA1A protein P0DMV8 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21730050 t gcesareni Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex SIGNOR-251668 0.633 BKM120 chemical CHEBI:71954 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190386 0.8 RUNX2 protein Q13950 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 f miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. SIGNOR-254552 0.256 PIEZO1 protein Q92508 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). SIGNOR-262571 0.388 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 t llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  SIGNOR-251059 0.351 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17012224 t miannu Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. SIGNOR-259910 0.646 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation Ser215 ESLSTHTsPSQSPNS 9606 16138080 t lperfetto We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes SIGNOR-140143 0.2 GNAI2 protein P04899 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 t TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation SIGNOR-256492 0.2 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 0.7 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser300 SMSDPGVsYRTREEI -1 11486000 t lperfetto Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes. SIGNOR-109651 0.871 1038915-60-4 chemical CID:24958200 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194402 0.8 LRRK2 protein Q5S007 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 22303461 t gcesareni Lrrk2 directly phosphorylates tubulin-associated tau, but not free tau;(iii) lrrk2 phosphorylates tau at thr181 as one of the target sites;. furthermore, we revealed that lrrk2-mediated phosphorylation of tau reduces its tubulin-binding ability. SIGNOR-195756 0.528 HRAS protein P01112 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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-252689 0.845 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 0.261 RBPJ protein Q06330 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 21873209 t gcesareni When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects. SIGNOR-176200 0.877 GDF11 protein O95390 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 12414726 t gcesareni Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2 SIGNOR-95309 0.625 CH5132799 chemical CID:49784945 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252648 0.8 CSRP3 protein P50461 UNIPROT MYF6 protein P23409 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 t 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. SIGNOR-241096 0.446 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 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].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf SIGNOR-202796 0.389 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 0.7 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 0.327 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr178 EEAERKLySGAQTDG 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251392 0.619 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni Caspase-3 is required for the activation of caspases 6 SIGNOR-256467 0.619 pimozide chemical CHEBI:8212 ChEBI STAT5A protein P42229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001545 23264850 t miannu We have identified the psychotropic drug pimozide as an effective inhibitor of STAT5 function. Pimozide inhibits the tyrosine phosphorylation of STAT5, leading to the death of AML cells through the induction of apoptosis. SIGNOR-260125 0.8 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000195 17289681 t The effect has been demonstrated using P34152-3 gcesareni We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress. SIGNOR-152971 0.649 FANCL protein Q9NW38 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 SIGNOR-C300 17396147 t lperfetto Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263250 0.9 SYVN1 protein Q86TM6 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29731393 t miannu NRF2 is negatively regulated by three E3 ubiquitin ligase complexes: the KEAP1-CUL3-RBX1 complex, the β-TrCP-SKP1-CUL1-RBX1 complex, and HRD1. SIGNOR-267360 0.2 CSNK2A1 protein P68400 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Thr236 VEKFKDNtIPDKVKK 9606 15064744 t lperfetto Inhibition of protein kinase ck2 enzyme activity in vivo resulted in an enhanced nuclear localization of cdc25c. Thus, phosphorylation of cdc25c at threonine 236 is an important signal for the retention of cdc25c in the cytoplasm SIGNOR-123713 0.302 AKT1 protein P31749 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-217670 0.602 apraclonidine chemical CHEBI:2788 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation -1 8784451 t miannu we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier. SIGNOR-258498 0.8 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207779 0.8 CH5132799 chemical CID:49784945 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190943 0.8 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 0.8 TFE3 protein P19532 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells SIGNOR-276821 0.324 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 0.2 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 0.894 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 3930339 t ulcerative colitis gcesareni SIGNOR-251702 0.8 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 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-107420 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI WDR45B protein Q5MNZ6 UNIPROT up-regulates activity chemical activation 9606 BTO:0001938 28561066 t miannu All WIPI members fold into seven-bladed β-propeller proteins that bind PtdIns3P and co-localize at nascent autophagosomes. SIGNOR-268476 0.8 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 0.73 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-260086 0.317 GSK3A protein P49840 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 35487243 t miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 SIGNOR-275398 0.632 N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide chemical CHEBI:91389 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189525 0.8 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 0.516 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 0.8 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 0.2 4-(4-fluoronaphthalen-1-yl)-6-isopropylpyrimidin-2-amine chemical CID:196968 PUBCHEM HTR2B protein P41595 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206658 0.8 CDK5RAP2 protein Q96SN8 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19282672 t Giulio These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter SIGNOR-260313 0.309 PIK3R3 protein Q92569 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9415396 t gcesareni The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha SIGNOR-252723 0.742 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Thr221 KDEILPTtPISEQKG 9606 19059439 t Manara Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA SIGNOR-260895 0.2 SIRT1 protein Q96EB6 UNIPROT 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI up-regulates quantity chemical modification 9606 18662546 t miannu The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. SIGNOR-267963 0.8 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14993291 f gcesareni Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes SIGNOR-123087 0.685 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser23 WNLENRFsGWYDADL 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-91606 0.254 PER2 protein O15055 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 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-256371 0.7 KDM5B protein Q9UGL1 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 31776402 t lperfetto Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. SIGNOR-273450 0.309 EPHB3 protein P54753 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates activity phosphorylation Tyr614 VYIDPFTyEDPNEAV -1 9674711 t Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site. SIGNOR-251126 0.2 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 0.2 CEP43 protein O95684 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates relocalization 9606 16314388 t miannu Fop also binds to eb1 and is required for localizing eb1 to the centrosome SIGNOR-142400 0.2 NGFR protein P08138 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14699954 f amattioni Neurotrophin binding to p75ntr has also been shown to induce apoptosis SIGNOR-256655 0.7 TLR9 protein Q9NR96 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266749 0.439 PGLS protein O95336 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI down-regulates quantity chemical modification 9606 31586547 t miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). SIGNOR-267057 0.8 MAML1 protein Q92585 UNIPROT CCNT1 protein O60563 UNIPROT up-regulates relocalization 9606 15546612 t gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130712 0.2 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto Raptor phosphorylation by ULK1 was sufficient to completely block Rheb-induced mTORC1 activity in cells as well as mTORC1 kinase activity invitro SIGNOR-209910 0.573 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A2 protein P23975 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-257946 0.8 HOXC13 protein P31276 UNIPROT FOXN1 protein O15353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21191399 f miannu Hoxc13-dependent activation of foxn1 is part of a regulatory cascade controlling the expression of terminal differentiation markers. SIGNOR-170850 0.526 CEBPA protein P49715 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-254043 0.335 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT up-regulates activity phosphorylation Tyr1055 VPEGHEYyRVREDGD 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-43092 0.2 ANKRD26 protein Q9UPS8 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 21669876 f lperfetto Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts. SIGNOR-266071 0.7 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 0.362 NR2C2 protein P49116 UNIPROT LHCGR protein P22888 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000318 10644740 t Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. SIGNOR-266217 0.2 AMER1 protein Q5JTC6 UNIPROT WT1 protein P19544 UNIPROT up-regulates binding 9606 19416806 t miannu Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors. SIGNOR-185644 0.437 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 0.2 KIF7 protein Q2M1P5 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by stabilization binding 10090 19549984 t lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. SIGNOR-209608 0.622 SMC3 protein Q9UQE7 UNIPROT MXD3 protein Q9BW11 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-241281 0.296 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 0.94 tri-mu-sulfido-mu3-sulfido-triiron chemical CHEBI:21137 ChEBI Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-267734 0.8 SP2 protein Q02086 UNIPROT IRF1 protein P10914 UNIPROT up-regulates activity binding 9606 BTO:0000552 19482358 t miannu Sp2 could be also able to interact with IRF-1 and this interaction is also observed on DNA indicating that by this way Sp2 is able to modulate IRF-1 transcriptional activity. SIGNOR-226478 0.339 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR 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-259453 0.8 canagliflozin chemical CHEBI:73274 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190850 0.8 NSD1 protein Q96L73 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates methylation 9606 20080798 t lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-217388 0.463 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr8 MEELQDDyEDMMEEN 9606 10942405 t llicata Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites. SIGNOR-80792 0.451 AKT1 protein P31749 UNIPROT ATXN1 protein P54253 UNIPROT up-regulates quantity by stabilization phosphorylation Ser775 ATRKRRWsAPESRKL 9606 BTO:0000567 12757707 t Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. SIGNOR-252561 0.411 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 15905173 t lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain SIGNOR-137251 0.2 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C).  SIGNOR-276836 0.254 GMPS protein P49915 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 24462112 t miannu In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex. SIGNOR-204409 0.378 EEF2 protein P13639 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30082469 f gianni … several key regulators of nervous system translation, including eukaryotic initiation factor 2α (eIF2α), the mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1), and the eukaryotic elongation factor 2 (eEF2). These pathways regulate the overall rate of protein synthesis in neurons and have selective effects on the translation of specific messenger RNAs (mRNAs SIGNOR-268628 0.7 CYC-116 chemical CID:6420138 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191221 0.8 NFYC protein Q13952 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 BTO:0000801;BTO:0000876 9885213 t lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. SIGNOR-63019 0.966 ITLN1 protein Q8WWA0 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 35186726 f ITLN1 increases Akt phosphorylation in adipocytes, osteoblasts, and mesenchymal cells. |n mesenchymal stem cells, ITLN1 also leads to Akt-mediated proliferation, resistance to oxidative stress, and secretion of proangiogenic factors SIGNOR-272499 0.313 DIABLO protein Q9NR28 UNIPROT CASP9 protein P55211 UNIPROT up-regulates 9606 10929711 f gcesareni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-80215 0.736 PKI-402 chemical CID:44187953 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206253 0.8 PDHA2 protein P29803 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-267832 0.67 JUN protein P05412 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20338993 f miannu The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13. SIGNOR-254539 0.394 SNAI2 protein O43623 UNIPROT HPGD protein P15428 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004078 17575121 f miannu the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. SIGNOR-255172 0.264 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 0.592 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 0.49 MMP11 protein P24347 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272356 0.7 TGFBR1 protein P36897 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex SIGNOR-62868 0.631 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 0.385 CDS1 protein Q92903 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267018 0.8 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 15069075 t gcesareni Thus, pkc-zeta might promote feedback ir/irs-1 complex formation and irs-1 tyrosine phosphorylation through phosphorylation of ser318. SIGNOR-123738 0.723 SP1 protein P08047 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11867220 f miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. SIGNOR-255199 0.318 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 0.8 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 0.8 2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylidene]propanedinitrile chemical CHEBI:93757 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189368 0.8 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 0.8 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 0.2 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr438 LYKRNFDtGLQEYKS 9606 21545357 t lperfetto Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. SIGNOR-173643 0.2 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 0.8 CCL1 protein P22362 UNIPROT CCR8 protein P51685 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000785 12645948 t gcesareni Ccl1 activates the mapk pathway in ccr8-transfected cho cells. SIGNOR-99401 0.726 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 0.325 RHAG protein Q02094 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266020 0.403 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 0.478 SIRT4 protein Q9Y6E7 UNIPROT GLUD1 protein P00367 UNIPROT down-regulates activity glycosylation 9606 16959573 t miannu We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. SIGNOR-267828 0.62 PEX14 protein O75381 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding -1 15798189 t miannu The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7. SIGNOR-253027 0.929 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-193378 0.736 NR3C1 protein P04150 UNIPROT KAT2B protein Q92831 UNIPROT up-regulates activity relocalization 32917954 t SimoneGraziosi NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase SIGNOR-269233 0.549 TBX2 protein Q13207 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 f TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells SIGNOR-251562 0.7 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates guanine nucleotide exchange factor 9606 10982832 t miannu Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases. SIGNOR-81645 0.761 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 0.433 MLF1 protein P58340 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 15861129 f miannu Mlf1 induces p53-dependent cell cycle arrest SIGNOR-135943 0.289 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 11910029 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-249148 0.439 MAPK1 protein P28482 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation -1 8929531 t lperfetto The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL. SIGNOR-44858 0.461 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 0.679 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 t amattioni Crk could bind to both pdgf alpha- and beta-receptors in vivo SIGNOR-75884 0.609 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 0.951 VARS1 protein P26640 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270527 0.8 IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 22810696 t lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. SIGNOR-251495 0.821 RABEP1 protein Q15276 UNIPROT RABGEF1 protein Q9UJ41 UNIPROT up-regulates binding 9606 11452015 t miannu We show that rabaptin-5 increases the exchange activity of rabex-5 on rab5. SIGNOR-109395 0.942 FOXO3 protein O43524 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-217887 0.7 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 0.698 IFNG protein P01579 UNIPROT RFX5 protein P48382 UNIPROT up-regulates activity 9606 BTO:0000567 9177217 f 2 miannu Transcriptional Activation by the RFX5 Activation Domain Is IFN-_-Inducible in HeLa Cells. SIGNOR-241368 0.283 BCL2L1 protein Q07817 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax SIGNOR-152983 0.748 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL -1 15946941 t done miannu PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity SIGNOR-274081 0.2 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 0.395 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 0.28 Caspase 3 complex complex SIGNOR-C221 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 t lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. SIGNOR-256455 0.536 MRPS6 protein P82932 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-261440 0.708 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258105 0.8 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0003316 10781582 t lperfetto Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner[...]These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo. SIGNOR-226614 0.773 BRSK1 protein Q8TDC3 UNIPROT WEE1 protein P30291 UNIPROT unknown phosphorylation Ser642 KKMNRSVsLTIY -1 15150265 t llicata HsSAD1 protein produced in Sf9 cells phosphorylated the GST-fused human wild-type Wee1A fragment but not its S642A mutant produced inEscherichia coli (Fig. 2). The kinase-dead hsSAD1 mutant (K59A) failed to phosphorylate the wild-type Wee1A fragment. SIGNOR-250601 0.439 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 6749443 t bronchial ashma gcesareni SIGNOR-251696 0.8 PRKCA protein P17252 UNIPROT NOXO1 protein Q8NFA2 UNIPROT up-regulates phosphorylation Thr346 AIQSRCCtVTRRALE 9606 23957209 t llicata Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation. SIGNOR-202482 0.2 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 0.2 Av/b6 integrin complex SIGNOR-C179 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-269028 0.7 PAK1 protein Q13153 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-205110 0.417 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 0.591 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT unknown phosphorylation Tyr707 DVYSTDYyRVGGHTM 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. SIGNOR-250207 0.2 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 0.384 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 0.757 TRIM8 protein Q9BZR9 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity polyubiquitination Lys158 ALIHRDLkPPNLLLV 22084099 t K63 miannu These results suggest that TRIM8 could mediate K63-linked polyubiquitination of TAK1 at residue K158.These results suggest that TRIM8 is involved in TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked TAK1 polyubiquitination and subsequent activation. SIGNOR-271890 0.343 ARHGEF5 protein Q12774 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-260533 0.617 MTF1 protein Q14872 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 f miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. SIGNOR-254601 0.286 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207302 0.8 RBX1 protein P62877 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-154511 0.868 PIAS4 protein Q8N2W9 UNIPROT SMAD4 protein Q13485 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-104541 0.558 MMP14 protein P50281 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272382 0.7 PELI1 protein Q96FA3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates quantity by expression ubiquitination 9606 17997719 t lperfetto These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells. SIGNOR-159055 0.767 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 0.7 ASIP protein P42127 UNIPROT ATRN protein O75882 UNIPROT up-regulates binding 9606 BTO:0001253 11137996 t gcesareni Attractin is a low-affinity receptor for agouti protein, but not agrp, in vitro and in vivo. SIGNOR-85496 0.391 CHM protein P24386 UNIPROT RABGGTA protein Q92696 UNIPROT down-regulates activity binding 9606 BTO:0000007 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. SIGNOR-265570 0.77 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 0.8 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 0.299 EFNA2 protein O43921 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 10072375 t tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) SIGNOR-65416 0.818 AMPK complex SIGNOR-C15 SIGNOR EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 22669845 t lperfetto In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation SIGNOR-216503 0.425 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser659 FHGAEVYsDSEDDVL 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-184151 0.635 IFNB1 protein P01574 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-105934 0.675 FARP2 protein O94887 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19276662 f Regulation of expression miannu FIR induced the expression of IAP1, IAP2, XIAP Survivin, MnSOD, TNFalpha, pAKT and IL-1alpha SIGNOR-251761 0.2 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 0.755 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 0.61 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 0.638 PAMPs stimulus SIGNOR-ST11 SIGNOR FCN3 protein O75636 UNIPROT up-regulates activity binding -1 11907111 t lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. SIGNOR-263406 0.7 CSNK2A1 protein P68400 UNIPROT ABCF1 protein Q8NE71 UNIPROT unknown phosphorylation Ser140 AALIQDQsEEEEEEE 9606 17894550 t gcesareni We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2. SIGNOR-157937 0.2 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 0.837 PRKCD protein Q05655 UNIPROT FSCN1 protein Q16658 UNIPROT down-regulates activity phosphorylation Ser39 KVNASASsLKKKQIW 9606 BTO:0000931 8647875 t lperfetto Phosphorylation of human fascin inhibits its actin binding and bundling activities. SIGNOR-248944 0.324 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 0.7 AKT1 protein P31749 UNIPROT 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-252488 0.435 TP53 protein P04637 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 15077116 t gcesareni P53 interacts with the pro-apoptotic mitochondrial membrane protein bak SIGNOR-124122 0.691 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 0.323 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 0.291 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 9668047 t gcesareni Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer. SIGNOR-59137 0.594 PRKACA protein P17612 UNIPROT KCNJ12 protein Q14500 UNIPROT down-regulates activity phosphorylation Ser431 QRPYRREsEI 9534 11181181 t miannu Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚  SIGNOR-249998 0.283 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 0.8 GDNF protein P39905 UNIPROT PDPK1 protein O15530 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-252186 0.2 CDON/SPAG9 complex SIGNOR-C21 SIGNOR ABL1 protein P00519 UNIPROT unknown binding 9606 19470755 t lperfetto We report that abl associates with both cdo and jlp during myoblast differentiation SIGNOR-217019 0.523 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS. SIGNOR-268789 0.8 DHRS9 protein Q9BPW9 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265117 0.8 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 0.748 AKT1 protein P31749 UNIPROT 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-252503 0.297 ICAM4 protein Q14773 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266019 0.334 CSNK1D protein P48730 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1479 SSSSTKGtYFPAILN 9606 35487243 t miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 SIGNOR-275402 0.2 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 0.576 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 t Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. SIGNOR-260307 0.646 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 0.66 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 0.273 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 0.904 STAG proteinfamily SIGNOR-PF52 SIGNOR 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-263314 0.919 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 0.598 SIRT1 protein Q96EB6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. SIGNOR-252456 0.6 TTM complex complex SIGNOR-C305 SIGNOR Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates activity relocalization 27025256 t lperfetto Terb1 and Sun1 are two key proteins linking the meiotic telomeres to the NE. Terb1 participates in telomere fortification by recruiting cohesins to the site SIGNOR-263307 0.2 CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 11884404 f fferrentino Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. SIGNOR-250564 0.7 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 9430701 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-54943 0.8 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8702807 f gcesareni This result suggests that the p38mapk cascade could be involved in the negative regulation of cyclin d1 transcription and thus antagonize the mitogen-dependent stimulation of cyclin d1 transcription mediated, at least in part, by the p42/p44mapk cascade. SIGNOR-43096 0.426 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 0.458 PIM3 protein Q86V86 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273897 0.2 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 9091312 t lperfetto Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259 SIGNOR-216616 0.298 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 0.8 AKT2 protein P31751 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 BTO:0000150 20231902 t inferred from 70% of family members gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-269937 0.262 ITCH protein Q96J02 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates ubiquitination 9606 BTO:0001253 10940313 t gcesareni Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain. SIGNOR-254331 0.644 PTPN1 protein P18031 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation 9606 15780598 t lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. SIGNOR-134564 0.646 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser56 NDDPLLRsAGKVRDI 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-266416 0.371 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. SIGNOR-256233 0.7 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 0.2 NEXMIF protein Q5QGS0 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000938 27822498 f miannu Xpn regulates N-cadherin and β1-integrin expression at the transcriptional level in PC12 cells SIGNOR-269660 0.2 FGF12 protein P61328 UNIPROT SCN4A protein P35499 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-253432 0.255 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys28 LATKAARkSAPATGG 9606 24987060 t miannu The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A). SIGNOR-260449 0.2 MRAP protein Q8TCY5 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252366 0.474 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 BTO:0000142 16401070 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. 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-143485 0.2 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 0.723 U0126.EtOH chemical CHEBI:90692 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244961 0.8 ABL1 protein P00519 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 11593427 t gcesareni Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation. SIGNOR-245365 0.41 VAPB protein O95292 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-262118 0.606 IL17B protein Q9UHF5 UNIPROT IL17RB protein Q9NRM6 UNIPROT up-regulates binding 9606 BTO:0000130 BTO:0000975;BTO:0000142;BTO:0000671 10749887 t gcesareni Here we report on the discovery of a novel il-17 homolog (il-17b), together with the identification of a novel cell surface receptor that specifically binds to it. We detail the molecular cloning, tissue distribution, and expression of both il-17b and il-17br, describe thein vivo activity of il-17b, and demonstrate binding to il-17br. SIGNOR-76544 0.748 HP protein P00738 UNIPROT hb:hp complex SIGNOR-C149 SIGNOR form complex binding 9606 11854029 t miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. SIGNOR-255283 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 20419129 t lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. SIGNOR-165026 0.2 Neuronal AP-3 complex SIGNOR-C445 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t miannu 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-268525 0.342 DAXX protein Q9UER7 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates binding 9606 23405218 t gcesareni The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53. SIGNOR-200892 0.673 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 0.2 AARS1 protein P49588 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 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-270447 0.8 DCK protein P27707 UNIPROT 2'-deoxyadenosine 5'-monophosphate(2-) smallmolecule CHEBI:58245 ChEBI up-regulates quantity chemical modification 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-275808 0.8 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser7 sSSSYRRM -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-250071 0.309 TMED5 protein Q9Y3A6 UNIPROT TMED10 protein P49755 UNIPROT up-regulates activity binding 9606 BTO:0000567 19948005 t Sara P28 forms hetero-oligomeric complexes with p23. p23 is a major determinant for efficient targeting of p28 to the ERGIC SIGNOR-261298 0.568 PKA proteinfamily SIGNOR-PF17 SIGNOR AQP2 protein P41181 UNIPROT up-regulates activity phosphorylation Ser256 REVRRRQsVELHSPQ 9615 BTO:0000837 12194985 t lperfetto For Ser-256 in AQP2, this hypothesis is in line with data from Zeleninaet al. (35), who showed that in isolated rat inner medulla prostaglandin E2 induces internalization of AQP2 without decreasing the amount of PKA-phosphorylated AQP2.|Phosphorylation of Ser-256 Is Necessary and Sufficient for Localization of AQP2 in the Apical Plasma Membrane SIGNOR-264563 0.2 MAP4K3 protein Q8IVH8 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation Thr538 LGDAKTNtFCGTPDY 9606 BTO:0000782 21983831 t llicata We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling. SIGNOR-176744 0.38 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr406 DASSQDCyDIPRAFP 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-236396 0.76 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT down-regulates binding 9606 10196546 t gcesareni Semaphorins a and e act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. SIGNOR-66661 0.913 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-252509 0.356 CDK5 protein Q00535 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser75 NSSDTVTsPQRAGPL 9606 BTO:0000938 10544291 t llicata These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development. SIGNOR-71950 0.39 MEF2C protein Q06413 UNIPROT MECP2 protein P51608 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-254025 0.346 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 0.375 PLAGL2 protein Q9UPG8 UNIPROT SFTPC protein P11686 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000353 17618602 f miannu nuclear PLAGL2 occupied and transactivated the endogenous SP-C promoter in lung cells. SIGNOR-254927 0.298 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 0.427 RXRB protein P28702 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-81455 0.636 GOT1 protein P17174 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-268062 0.8 SMAD7 protein O15105 UNIPROT SMURF proteinfamily SIGNOR-PF29 SIGNOR up-regulates activity relocalization 9606 19352540 t lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. SIGNOR-253258 0.898 selumetinib chemical CHEBI:90227 ChEBI MAP2K2 protein P36507 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-258281 0.8 ROCK2 protein O75116 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Thr14 KKQFHKAtQKVSEKV 9606 16164598 t llicata We identified the phosphorylation site of endophilin a1 at thr-14 endophilin t14d inhibited egf receptor internalization. Furthermore, phosphorylation of endophilin by rho-kinase inhibited the binding to cin85. SIGNOR-140466 0.439 MAPK3 protein P27361 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Ser745 KSRQNLQsPTSSRAT 9606 BTO:0000007 17804409 t esanto Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist. SIGNOR-157711 0.354 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 0.777 VHL protein P40337 UNIPROT IREB2 protein P48200 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0003781 15777842 t miannu We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2. SIGNOR-271421 0.359 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 0.362 RBPJ protein Q06330 UNIPROT GTF2A2 protein P52657 UNIPROT up-regulates binding 9606 9620850 t Inhibits transcription gcesareni Rbp interacts with two transcriptional coactivators: dtafii110, a subunit of tfiid, and tfiia to repress transcription. The domain of dtafii110 targeted by rbp is the same domain that interacts with tfiia SIGNOR-57832 0.2 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 11910029 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-249147 0.439 AKT1 protein P31749 UNIPROT ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata Akt phosphorylates s554 in acap1 SIGNOR-252483 0.483 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity precursor of 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-268675 0.8 RXRB protein P28702 UNIPROT NR2F2 protein P24468 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-79452 0.275 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 0.8 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206364 0.8 15(S)-HETE smallmolecule CHEBI:15558 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 12517954 t lperfetto 15(S)-HETE is a ligand for PPARγ in IL-4-stimulated A549 cells SIGNOR-254095 0.8 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 0.7 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 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR SMN1 protein Q16637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 19103745 t lperfetto PKA increases SMN complex formation and SMN stability.|As expected, SMN was phosphorylated by PKA (Fig. ​(Fig.6D).6D). SIGNOR-253114 0.2 atomoxetine chemical CHEBI:127342 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition -1 9871604 t miannu The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. SIGNOR-259071 0.8 ELP1 protein O95163 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 12058026 f gcesareni Ikap efficiently and specifically enhanced jnk activation induced by ectopic expression of mekk1 and ask1, upstream activators of jnk SIGNOR-89334 0.2 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength 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-235721 0.923 BCL2L1 protein Q07817 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17446862 t gcesareni The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy. SIGNOR-154480 0.915 TNFSF15 protein O95150 UNIPROT TNFRSF25 protein Q93038 UNIPROT up-regulates binding 9606 14585074 t amattioni The ligand of dr3 is tl1a SIGNOR-103078 0.776 INSR protein P06213 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 10803466 t gcesareni Insulin induces the ir-grb7 interaction in cells expressing physiological levels of the proteins, suggesting that grb7 is implicated in insulin signaling. SIGNOR-77153 0.418 POLDIP3 protein Q9BY77 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-268515 0.618 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1054 FGLARDIyKDPDYVR 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-248709 0.699 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 0.375 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 0.8 RB1 protein P06400 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8242749 t gcesareni A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition. SIGNOR-37139 0.57 CD38 protein P28907 UNIPROT NMN(+) smallmolecule CHEBI:14648 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide SIGNOR-264252 0.8 SMAD6 protein O43541 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 11737269 t lperfetto Smad6 interacts with tak1 and tab1, and smad7 with tab1 SIGNOR-112636 0.2 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206835 0.8 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 0.584 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101332 0.96 VARLITINIB chemical CID:42642648 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189903 0.8 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0000567 9001210 t Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2 lperfetto Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory. SIGNOR-45729 0.752 FOXI1 protein Q12951 UNIPROT CFTR protein P13569 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20972246 f miannu Results of transiently transfected vas deferens cells with either the -33G wild-type or the -33A variant CFTR directed luciferase reporter gene confirmed that the -33A variant, which alters the FOXI1 (Forkhead box I1) binding, significantly decreases the CFTR promoter activity. SIGNOR-254176 0.253 dabrafenib chemical CHEBI:75045 ChEBI NEK9 protein Q8TD19 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0005011 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-261072 0.8 SNCAIP protein Q9Y6H5 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 19224863 f miannu Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions SIGNOR-272596 0.7 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15109499 f lperfetto Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. SIGNOR-232174 0.438 KAT5 protein Q92993 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates acetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation. SIGNOR-170594 0.466 MDH1 protein P40925 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-268099 0.8 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT unknown phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 t llicata SCAMP3 Is Tyrosine Phosphorylated by EGFR in Vitro SIGNOR-251096 0.399 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252658 0.8 PPP4C protein P60510 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity dephosphorylation 9606 18347064 t miannu PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.|We also found that PP4c negatively regulates Cdk1 activity in interphase. SIGNOR-277162 0.397 FYN protein P06241 UNIPROT PGD protein P52209 UNIPROT up-regulates activity phosphorylation Tyr481 GTVSSSSyNA 9606 30824700 t lperfetto 6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP+ and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. SIGNOR-265758 0.2 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Ser241 RRIPYRYsDELNEII 9606 17197699 t gcesareni Enzymatic activity, inhibited; SIGNOR-151767 0.2 TRAF1 protein Q13077 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates binding 9606 8069916 t gcesareni Traf1 and traf2 can form homo- and heterotypic dimers. SIGNOR-34768 0.636 TLR4 protein O00206 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20596954 f fstefani Regulation of toll-like receptor signaling in the innate immunity. SIGNOR-166488 0.7 Vicriviroc Malate chemical CID:10218922 PUBCHEM CCR5 protein P51681 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207657 0.8 POLR3B protein Q9NW08 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-266132 0.863 bufexamac chemical CHEBI:31317 ChEBI HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 21258344 t Luana  We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. SIGNOR-257891 0.8 AKT2 protein P31751 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 SIGNOR-153327 0.2 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 0.512 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 0.8 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK10 protein P53779 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). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. SIGNOR-111980 0.8 RAE1 protein P78406 UNIPROT NUP98 protein P52948 UNIPROT up-regulates activity binding 9606 16036565 t miannu Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export. SIGNOR-260868 0.882 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 0.265 RAD51 protein Q06609 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-263206 0.736 N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide chemical CHEBI:94573 ChEBI EDNRA protein P25101 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207902 0.8 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 0.458 TRAF6 protein Q9Y4K3 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity ubiquitination 9606 BTO:0000007 28980855 t inferred from family member The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. SIGNOR-270271 0.2 CDK1 protein P06493 UNIPROT DUT protein P33316-2 UNIPROT up-regulates quantity phosphorylation Ser11 SEETPAIsPSKRARP -1 8631817 t miannu DUTPase Is Phosphorylated at a Consensus Cyclin-dependent Protein Kinase Site: in Vitro Phosphorylation of Ser-11 by p34cdc2. It is conceivable that the exclusive phosphorylation of DUT-N may play a role in nuclear targeting of this protein. Taken a step further, Ser-11 may confer the ability of DUT-N to localize in specific regions of the nucleus where the dUTPase function is required. The Ser-11 Ala mutant should aid in the testing of these hypotheses. SIGNOR-262693 0.386 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys694 SPLACTNkRPRPEGM 9606 21791603 t miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). SIGNOR-272732 0.581 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 0.288 CCP110 protein O43303 UNIPROT CETN2 protein P41208 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-265967 0.698 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189359 0.8 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 0.7 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 0.2 SMURF2 protein Q9HAU4 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR down-regulates ubiquitination 9606 22298955 t inferred from 70% of family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-269845 0.787 UBE3A protein Q05086 UNIPROT PSMD2 protein Q13200 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-265133 0.277 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 0.2 NFKB1 protein P19838 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-55375 0.713 SOCS1 protein O15524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 24890514 f apalma Socs1 associates with CSF-1R pTyr-697 and pTyr721 binding sites to inhibit proliferation by an unknown mechanism SIGNOR-255575 0.7 GAB2 protein Q9UQC2 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 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-252677 0.521 SOCS1 protein O15524 UNIPROT IFNG protein P01579 UNIPROT down-regulates 9606 21628332 f lperfetto SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease. SIGNOR-249571 0.556 USP1 protein O94782 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 34188037 t miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  SIGNOR-277308 0.2 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-252963 0.595 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 0.771 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 20577053 f gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. SIGNOR-252916 0.2 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 0.735 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity relocalization 9606 18596912 t inferred from 70% family members lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-270008 0.2 WNK4 protein Q96J92 UNIPROT SLC12A3 protein P55017 UNIPROT down-regulates activity 22342722 f lperfetto Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition SIGNOR-264632 0.579 CDH17 protein Q12864 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-265856 0.705 PIK3C3 protein Q8NEB9 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 10090 19270693 t lperfetto The beclin 1-vps34 interaction regulates autophagy. SIGNOR-184521 0.936 CASP8AP2 protein Q9UKL3 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates binding 9606 SIGNOR-C13 22075988 t gcesareni In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex. SIGNOR-177104 0.246 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207084 0.8 LYN protein P07948 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto Phosphorylation of FcgammaRIIa/c by Lyn is clearly dependent on the presence of Y-298, since all mutants lacking this residue are not phosphorylated by this PTK. This result suggests that Y-298 might be the only tyrosine residue of FcgammaRIIa/c phos- phorylated by Lyn. SIGNOR-249379 0.608 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 0.861 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 0.419 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 0.855 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT up-regulates activity phosphorylation Tyr391 PNVQRSDyLNTFEFM -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-267630 0.424 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 0.313 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 21317932 t gcesareni Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo. SIGNOR-172008 0.547 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 0.454 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 11113114 t gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. SIGNOR-85005 0.417 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 20940030 f gcesareni Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53. SIGNOR-168457 0.515 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 0.804 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr579 RYIEDEDyYKASVTR 9606 11337490 t lperfetto Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest SIGNOR-107502 0.544 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser170 SFKLSGFsFKKNKKE -1 1560845 t gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin SIGNOR-249670 0.73 DLG4 protein P78352 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-270905 0.477 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 19956600 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-161924 0.655 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 0.575 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 0.2 CSNK2A1 protein P68400 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT down-regulates activity phosphorylation Ser390 LFPVCHDsDESDTAK -1 25066127 t miannu This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. SIGNOR-276650 0.2 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI IKBKE protein Q14164 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190792 0.8 SMAD2 protein Q15796 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR form complex binding 9606 11389444 t gcesareni We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases. SIGNOR-108487 0.778 EXT1 protein Q16394 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR form complex binding 9606 11518722 t miannu Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs SIGNOR-109938 0.582 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72056 0.819 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 0.8 CAMK2A protein Q9UQM7 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser843 DVRLSRGsIDREDGS 9606 15845548 t gcesareni Furthermore, activated camkii directly phosphorylated the recombinant cooh-terminal region of fak at a residue equivalent to ser-843. SIGNOR-135631 0.272 TRADD protein Q15628 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 14585074 t amattioni Tradd recruits caspase-8 SIGNOR-118591 0.909 NCSTN protein Q92542 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 10993067 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-81936 0.941 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr703 DHAEAALyKNLLHSK 9606 10377264 t miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr SIGNOR-68643 0.2 TNFSF13 protein O75888 UNIPROT TNFRSF17 protein Q02223 UNIPROT up-regulates binding 9606 BTO:0000782 10973284 t gcesareni April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding. SIGNOR-81386 0.686 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159377 0.2 VX-745 chemical CHEBI:90528 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207684 0.8 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 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-253160 0.459 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 t llicata 14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642. SIGNOR-252494 0.764 F2R protein P25116 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 BTO:0000007 22972936 f inferred from 70% of family members milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-269860 0.2 CEBPA protein P49715 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 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-259966 0.7 INTS12 protein Q96CB8 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-261470 0.75 NFE2L2 protein Q16236 UNIPROT CAT protein P04040 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-254651 0.426 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT up-regulates quantity by expression 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 0.8 CHRM3 protein P20309 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257224 0.397 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 0.7 PTPN1 protein P18031 UNIPROT CAV1 protein Q03135 UNIPROT unknown dephosphorylation Tyr14 VDSEGHLyTVPIREQ -1 16388599 t The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1. SIGNOR-248430 0.573 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 0.2 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206667 0.8 CSNK2A1 protein P68400 UNIPROT SHOX protein O15266 UNIPROT up-regulates phosphorylation Ser106 EKREDVKsEDEDGQT 9606 16325853 t lperfetto We show also that casein kinase ii phosphorylates shox on serine 106 efficiently in vitro. S106a shox mutant, defective in phosphorylation, does not activate transcription and fails to induce cell-cycle arrest and apoptosis SIGNOR-142875 0.338 NEB protein P20929 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 21798082 t gcesareni Igf1-akt signaling, by inhibiting gsk3b, allows the interaction of n-wasp with the unphosphorylated nebulin;the consequent recruitment of n-wasp to the z-disk promotes actin nucleation and elongation of actin filaments. SIGNOR-175671 0.352 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR PRKN protein O60260 UNIPROT up-regulates activity binding 10090 BTO:0002572 phosphorylation: ser65 24784582 t The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. SIGNOR-270343 0.2 BTG2 protein P78543 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 21172304 f Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2. SIGNOR-253658 0.2 POU2AF1 protein Q16633 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates binding 9606 BTO:0000776 12727885 t miannu Obf1 enhances transcriptional potential of oct1. SIGNOR-100968 0.622 2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine chemical CID:49830260 PUBCHEM VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 23316025 t Luana Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively. SIGNOR-261093 0.8 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 0.563 vatalanib chemical CHEBI:90620 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207642 0.8 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. SIGNOR-81110 0.525 MMP28 protein Q9H239 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272395 0.7 SIRT2 protein Q8IXJ6 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates deacetylation 9606 BTO:0000887;BTO:0001103 12887892 t gcesareni Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities. SIGNOR-104251 0.376 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr284 CPGRDRRtEEENLRK 9606 20959462 t llicata Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity. SIGNOR-168749 0.719 TTK protein P33981 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Ttk phosphorylation of thr735 was associated with partial inhibition of nuclear targeting of c-abl. SIGNOR-181064 0.279 CASP1 protein P29466 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261747 0.32 4-(3-chloro-2-fluorophenoxy)-1-[[6-(2-thiazolylamino)-2-pyridinyl]methyl]-1-cyclohexanecarboxylic acid chemical CHEBI:125340 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194411 0.8 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates activity phosphorylation Ser966 GEDSVSGsQRISSIY 9606 BTO:0005521 11877376 t Atm phosphorylates Smc1 on serines 957 and 966 in vitro and in vivo, and expression of an Smc1 protein mutated at these phosphorylation sites abrogates the ionizing irradiation-induced S phase cell cycle checkpoint SIGNOR-255589 0.705 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207299 0.8 SETBP1 protein Q9Y6X0 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 22566606 f miannu Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors SIGNOR-197318 0.344 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193543 0.8 UBE2I protein P63279 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates sumoylation Lys25 PETGRTVkEPEGPPP 9606 19744555 t miannu Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2 SIGNOR-187901 0.698 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr96 QDHSHLLySTIPRMQ -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-246508 0.922 PPP2CA protein P67775 UNIPROT RAF1 protein P04049 UNIPROT up-regulates dephosphorylation 9606 BTO:0000671 16239230 t miannu Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1. SIGNOR-141170 0.592 AKT2 protein P31751 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t gcesareni Creb is a nuclear target for activation via the growth factor-dependent ser/thr kinase akt/pkb. When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. SIGNOR-62253 0.514 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 0.639 EXOC5 protein O00471 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-270780 0.917 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr516 PVIENPQyFGITNSQ 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc SIGNOR-250204 0.2 RELN protein P78509 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 17584923 f Luana Reln, encoding an extracellular signaling molecule essential for neuronal lamination and synaptic plasticity SIGNOR-265772 0.7 COL2A1 protein P02458 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates activity binding 9606 BTO:0000249 25169886 t lperfetto Isolation, cloning, and sequence analysis of the integrin subunit alpha10, a beta1-associated collagen binding integrin expressed on chondrocytes. SIGNOR-253347 0.49 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 0.477 KCNIP4 protein Q6PIL6 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 8355 BTO:0000964 24811166 t Luisa KChIP4 increased the current amplitude of Kv4.2, decelerated the inactivation, and accelerated the recovery from inactivation of Kv4.2. KChIP.is known to promote the translocation of Kv4.2 from the endoplasmic reticulum or Golgi to the cell surface SIGNOR-269004 0.773 PAK1 protein Q13153 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 10092231 t miannu P21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity.  SIGNOR-250317 0.556 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 0.491 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 0.8 BACH1 protein O14867 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000150 22875853 f Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis SIGNOR-259337 0.7 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248294 0.424 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD2 protein P04179 UNIPROT up-regulates activity chemical activation 1542024 t lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase SIGNOR-272300 0.8 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 0.412 MYC protein P01106 UNIPROT CDKN2A protein P42771 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-102743 0.766 HSD17B2 protein P37059 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -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-269764 0.8 PAM protein P19021 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates activity cleavage 9606 23084901 t lperfetto Nevertheless, overall the results of this study show that peptide sequence recognition is an important aspect of the interactions of the prohormone substrates prooxytocin (3d) and procalcitonin (7e) with PAM, which is mirrored in the potency of analogous peptidomimetic glycolate inhibitors of the enzyme. SIGNOR-268551 0.2 PPP2R5B protein Q15173 UNIPROT CASP3 protein P42574 UNIPROT up-regulates dephosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 15569672 t gcesareni Dephosphorylation of caspase-3 at ser150 site by pp2a increased caspase-3 activity,which was essential to trigger apoptosis in neutrophils. SIGNOR-131435 0.2 NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). SIGNOR-262141 0.7 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227874 0.895 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser664 QSAFAGFsFVNPKFE 9606 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-248639 0.377 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120112 0.311 BCOR protein Q6W2J9 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0000007 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-252236 0.377 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 0.291 ATG2B protein Q96BY7 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001938 28561066 f 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-268486 0.7 PGK1 protein P00558 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-266505 0.8 YY1 protein P25490 UNIPROT COX7C protein P15954 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9092564 f miannu Mutation of both YY1 sites eliminates most of the promoter activity. Mutation at the upstream YY1 site significantly reduces the efficiency of transcript initiation at the major start site and thus plays the dominant role in COX7C regulation. SIGNOR-255617 0.257 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776;BTO:0003076 8816467 f lperfetto Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis SIGNOR-43927 0.461 PELI2 protein Q9HAT8 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates ubiquitination 9606 17997719 t gcesareni These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4. SIGNOR-159058 0.781 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBA1A protein Q71U36 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-259255 0.8 CSNK2A1 protein P68400 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-250911 0.339 mifepristone chemical CHEBI:50692 ChEBI NR3C1 protein P04150 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258709 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 26865625 t miannu  In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. SIGNOR-266770 0.2 KIFC1 protein Q9BW19 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 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-266117 0.7 EP300 protein Q09472 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-143399 0.822 DUSP10 protein Q9Y6W6 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 10391943 t gcesareni Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk SIGNOR-68986 0.705 CEBPG protein P53567 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-225015 0.2 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9534 BTO:0004055 10196136 t lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. SIGNOR-227917 0.712 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 18840653 t gcesareni Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well. SIGNOR-181546 0.566 EIF1B protein O60739 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity relocalization 9606 20921384 t lperfetto Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning SIGNOR-269145 0.463 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 0.76 E2F1 protein Q01094 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23542036 f miannu We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter. SIGNOR-253841 0.2 MAPK3 protein P27361 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-90533 0.739 SRC protein P12931 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1311 DSKVDLIyQNTTAMT 9606 BTO:0000007 22898603 t miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. SIGNOR-276373 0.636 NLRP3 protein Q96P20 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 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-256410 0.746 SLC2A3 protein P11169 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 23506862 t miannu GLUThe SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose T1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. SIGNOR-267461 0.8 MMP1 protein P03956 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272377 0.7 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 0.402 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 0.744 SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-253265 0.2 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 t gcesareni Bmk1 activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2. SIGNOR-113773 0.8 UPF2 protein Q9HAU5 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 31636381 f miannu Our data indicate that proper synaptic plasticity and cognitive function requires UPF2.  SIGNOR-265235 0.7 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 0.2 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 0.91 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser363 LSPVAPLsPARLQGP 9606 9130707 t gcesareni Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase. SIGNOR-47685 0.379 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 t lperfetto Sik2 could phosphorylate ser(794) of human irs-1 SIGNOR-99059 0.567 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 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-118890 0.2 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser1985 DSVTRATsDNLQVRG 28882890 t Phosphosite is derived from Figure 2 lperfetto C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation| Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. SIGNOR-275783 0.492 NEDD4L protein Q96PU5 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253457 0.292 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 0.478 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 0.728 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 0.8 YY1 protein P25490 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15291746 f miannu These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity. SIGNOR-255619 0.2 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17012224 t miannu Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. SIGNOR-259909 0.684 GSK3A protein P49840 UNIPROT ANKRD28 protein O15084 UNIPROT down-regulates activity phosphorylation Ser1007 INRYTNTsKTVSFEA -1 phosphorylation:Ser1011 TNTSKTVsFEALPIM 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-264792 0.2 LGALS3 protein P17931 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 f miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. SIGNOR-261905 0.255 MMP12 protein P39900 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-272357 0.7 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 0.416 NEK6 protein Q9HC98 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273894 0.2 NOTCH1 protein P46531 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11591772 f lperfetto Nf-kappab activity is regulated by notch-1 via transcriptional control of nf-kappab. SIGNOR-110963 0.377 PTPRO protein Q16827 UNIPROT VCP protein P55072 UNIPROT down-regulates activity dephosphorylation 9606 23533167 t miannu An important aspect of this study is that tyrosine dephosphorylation of VCP by PTPRO sensitizes HepG2 cells to Doxorubicin, a chemotherapeutic drug commonly used for a variety of cancers. SIGNOR-277063 0.423 ETS1 protein P14921 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11175361 f miannu Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis SIGNOR-259869 0.7 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 0.551 DMTF1 protein Q9Y222 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 f Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261583 0.2 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser30 TPRSRERsPSPLRGN 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-137474 0.26 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 0.628 FLT3 protein P36888 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001103 23704355 f gcesareni Here we report the identification of flt3l (fms-like tyrokine kinase 3 ligand) signaling as a novel regulator of skeletal myogenesis SIGNOR-202105 0.7 SMO protein Q99835 UNIPROT GNB1 protein P62873 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-148537 0.385 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser291 DVHMVSDsDGDDFED 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-180891 0.2 ARF6 protein P62330 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 14565977 f miannu ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha SIGNOR-264908 0.7 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 0.7 KIF11 protein P52732 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 21969468 f lperfetto The C-terminal fragment interferes with the TPX2–Eg5 interaction, relieving the inhibition of TPX2 on Eg5 and generating the observed spindle lengthening. According to this model, TPX2 and Eg5 should localize to microtubules in the spindle midzone. SIGNOR-265098 0.7 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. SIGNOR-185215 0.364 CSNK2A2 protein P19784 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-250996 0.374 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 t PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. SIGNOR-269111 0.346 seliciclib chemical CHEBI:45307 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206562 0.8 CSNK2A2 protein P19784 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-275740 0.307 873837-23-1 chemical CID:46930994 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190470 0.8 CDK4 protein P11802 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176530 0.329 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. SIGNOR-85110 0.51 BACE1 protein P56817 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Asp616 EISEVKMdAEFRHDS 9606 10931940 t lperfetto Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. SIGNOR-261763 0.794 VASP protein P50552 UNIPROT ATIC protein P31939 UNIPROT up-regulates activity phosphorylation Tyr104 RVVACNLyPFVKTVA 9606 BTO:0002181 18845790 t miannu ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity.  SIGNOR-276172 0.342 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 0.2 CHEK2 protein O96017 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser376 PLLPRVSsYLVPIQF 9606 BTO:0001938 17101782 t lperfetto Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein SIGNOR-150746 0.721 RBPJ protein Q06330 UNIPROT CIR1 protein Q86X95 UNIPROT up-regulates binding 9606 9874765 t amattioni In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex. SIGNOR-62932 0.669 AKT1 protein P31749 UNIPROT 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-252544 0.782 HSP90AA1 protein P07900 UNIPROT PPP5C protein P53041 UNIPROT up-regulates binding 9606 15577939 t miannu Hsp90 causes substantial activation of ppp5 by competing for tpr_phosphatase domain contacts and allowing access to the catalytic site. SIGNOR-131564 0.771 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 0.714 EIF5B protein O60841 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity binding 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269121 0.625 HSP90AA1 protein P07900 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 t Here we show that the stability of the tumour suppressor folliculin (FLCN) depends on the chaperone function of Hsp90. SIGNOR-256505 0.305 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259241 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-252813 0.2 PRKACA protein P17612 UNIPROT TPH1 protein P17752 UNIPROT up-regulates activity phosphorylation Ser58 RKSKRRNsEFEIFVD -1 9109552 t miannu The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme. SIGNOR-250062 0.35 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189945 0.8 glutamic acid smallmolecule CHEBI:18237 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264752 0.7 JUN protein P05412 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-256363 0.953 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 23279204 f SARA G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs SIGNOR-260983 0.7 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 0.411 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 0.517 POU5F1 protein Q01860 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 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-253161 0.497 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265814 0.7 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 0.282 Avacopan chemical CID:49841217 PUBCHEM C5AR2 protein Q9P296 UNIPROT down-regulates activity binding 9606 31734405 t lperfetto CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients. SIGNOR-263474 0.8 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 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-250064 0.505 CACNA2D3 protein Q8IZS8 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 31746409 f miannu Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. SIGNOR-266854 0.7 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI PRIM2 protein P49643 UNIPROT up-regulates activity chemical activation 26083061 t lperfetto Human DNA primase, are Fe-S proteins. The loss of an iron-sulfur cluster in RAD3 helicase results in a failure to unwind DNA1 SIGNOR-262134 0.8 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). SIGNOR-59659 0.677 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates binding 9606 11544529 t fstefani Mal (myd88-adapter-like) is required for toll-like receptor-4 signal transduction. SIGNOR-110337 0.78 AMPK complex SIGNOR-C15 SIGNOR NAMPT protein P43490 UNIPROT up-regulates quantity 10090 18477450 f gcesareni Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt SIGNOR-238824 0.272 CREB1 protein P16220 UNIPROT NR2F1 protein P10589 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000152 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253792 0.271 CTSS protein P25774 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 11920402 f lperfetto Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. SIGNOR-253319 0.7 WASHC2C protein Q9Y4E1 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-261016 0.2 SLC24A4 protein Q8NFF2 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-264397 0.8 RAN protein P62826 UNIPROT XPOT protein O43592 UNIPROT up-regulates activity binding 9606 9660920 t miannu The first step in export appears to be the formation of a trimeric tRNA/exportin-t/RanGTP complex. tRNA and RanGTP bind to exportin-t in a highly cooperative manner: tRNA increases the affinity of exportin-t for RanGTP apparently 300-fold (Figure 5A); conversely, RanGTP has to increase the affinity of exportin-t for tRNA by the same factor. 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 SIGNOR-261392 0.815 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 0.861 MAPK3 protein P27361 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188143 0.391 NFKB1 protein P19838 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 t Luana  The effect of TNF-alpha on the Bmp4 promoter is mediated through NF-kB. SIGNOR-266086 0.2 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr785 NSLISSDyELLSDPT 9606 18250158 t lperfetto The phosphorylation of wt jak3 and y980f/y981f/y785f mutant jak3 is presumably mediated through autophosphorylation at distinct jak3 sites within this model systemhosphorylation of jak3 on y785 has been reported to create a binding site for the adaptor protein sh2b-beta SIGNOR-160660 0.2 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCA protein P17252 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191490 0.8 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207105 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser177 LITPGSGsIYSSPGL 9606 BTO:0000567 35469017 t miannu CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2). SIGNOR-276713 0.2 IL17RA protein Q96F46 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR form complex binding 9606 BTO:0001946 32024054 t lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. SIGNOR-261335 0.549 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 0.649 ARPC1A protein Q92747 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-251515 0.877 POU5F1 protein Q01860 UNIPROT FOXA2 protein Q9Y261 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-253165 0.426 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser280 VDGTGDTsSEEDEDE 9606 11278496 t lperfetto TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels SIGNOR-246630 0.678 PFDN1 protein O60925 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270932 0.95 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 0.365 RELA protein Q04206 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 t lperfetto 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-217655 0.85 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 0.2 SRC protein P12931 UNIPROT PBK protein Q96KB5 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr272 DFDDEAYyAALGTRP 9606 BTO:0000038 27016416 t miannu Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon SIGNOR-277217 0.395 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Thr1225 SRRPRLEtILSLLVS -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-274063 0.303 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1197 HIQTPMLsQEQAQPP 9606 15173573 t lperfetto Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp SIGNOR-125073 0.271 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 0.608 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 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-163953 0.8 MTOR protein P42345 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000661 34535949 t Barakat Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616 SIGNOR-275430 0.345 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Ser493 CPPECPEsLHDLMCQ 9606 BTO:0002181 33388549 t miannu Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation SIGNOR-277544 0.383 BTG2 protein P78543 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254650 0.2 ARNTL2 protein Q8WYA1 UNIPROT CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR form complex binding 19605937 t lperfetto Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription SIGNOR-253710 0.683 ABL1 protein P00519 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation Tyr805 RIPGGNIyISPLKSP 9606 BTO:0001271 16158058 t llicata Rb-induced apoptosis is compromised by abl-catalysed phosphorylation of rb at y805. SIGNOR-140396 0.57 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 23869758 t miannu On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2 SIGNOR-254405 0.569 ponatinib chemical CHEBI:78543 ChEBI RIPK3 protein Q9Y572 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000661 25801024 t Federica Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3 SIGNOR-261083 0.8 ICI D1694 chemical CHEBI:5847 ChEBI TYMS protein P04818 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206403 0.8 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 24841372 t lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways SIGNOR-205092 0.41 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 11700305 t lperfetto We identify catalytic domain fragments of protein kinase c (pkc) delta and pkcbetai/ii as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin cd18 chain. The sites phosphorylated in vitro were identified as ser-745 and thr-758. Pkc-mediated phosphorylation of cd18 after cell stimulation could lead to the recruitment of 14-3-3 proteins to the activated integrin, which may play a role in regulating its adhesive state or ability to signal. SIGNOR-111495 0.329 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 0.911 PRKACA protein P17612 UNIPROT PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser56 NLQLPPLsQRQSERA 9534 BTO:0000298 12441002 t miannu PKA-mediated phosphorylation of Ser-56 in UCR1 of PDE4B4 leads to activation of this long isoform SIGNOR-250024 0.605 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Thr275 LVDSKAKtRSAGCAA 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-51211 0.723 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 28531279 f miannu The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 SIGNOR-260328 0.365 RAB10 protein P61026 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-260618 0.418 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 0.415 CRYAA protein P02489 UNIPROT CRYBB2 protein P43320 UNIPROT up-regulates activity binding 9606 22982024 t miannu Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin. SIGNOR-252155 0.2 SLIT1 protein O75093 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis. SIGNOR-68327 0.382 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr250 NSCTPITtPELTTPC 9606 9155017 t lperfetto Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38. Erk and p38 phosphorylate MNK1 and Mnk2. SIGNOR-48342 0.672 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1248 PTAENPEyLGLDVPV -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251128 0.2 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 25010901 t gcesareni Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase SIGNOR-196740 0.81 MAML1 protein Q92585 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation 9606 17300219 t gcesareni We speculated that maml1, in addition to recruiting p300, might directly interact with histones to facilitate histone acetylation. We had observed acetylation of the histones h3 and h4. SIGNOR-153041 0.2 CENPX protein A8MT69 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-265201 0.2 LY294002 chemical CHEBI:65329 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 t gcesareni Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin. SIGNOR-252647 0.8 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9259419 t rheumatoid arthritis gcesareni SIGNOR-251695 0.8 SLC9A5 protein Q14940 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-265595 0.8 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 0.2 ERCC6 protein Q03468 UNIPROT NEIL1 protein Q96FI4 UNIPROT up-regulates activity binding 9606 19179336 t Regulation miannu CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells. SIGNOR-251931 0.344 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 0.26 GOPC protein Q9HD26 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 t gcesareni Npist binds beclin 1 by a ccd SIGNOR-171896 0.523 IGF2 protein P01344 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 11867533 t fspada Insulin-like growth factor ii receptor (igf2r) is a multifunctional cell surface receptor implicated in tumour suppression. Its growth inhibitory activity has been associated with an ability to bind igf-ii. SIGNOR-115250 0.727 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131634 0.656 UHRF1 protein Q96T88 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005192 20037778 f miannu we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. SIGNOR-254224 0.2 NRTN protein Q99748 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-49122 0.715 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203568 0.777 sirolimus chemical CHEBI:9168 ChEBI CD80 protein P33681 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255475 0.8 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 0.8 LAMB3 protein Q13751 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-253236 0.648 tamoxifen chemical CHEBI:41774 ChEBI GPER1 protein Q99527 UNIPROT up-regulates chemical activation 9606 15539556 t gcesareni The finding that the antiestrogens tamoxifen and ici 182,780, and an environmental estrogen, ortho,para-dichlorodiphenyldichloroethylene (o,p'-dde), have high binding affinities to the receptor and mimic the actions of e2 has important implications for both the development and treatment of estrogen-dependent breast cancer. SIGNOR-130395 0.8 MAP2K6 protein P52564 UNIPROT CRK protein P46108 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily. SIGNOR-42384 0.2 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 0.588 CSF3 protein P09919 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni The gcsf:gcsf-r complex formed a 2:2 stoichiometry by means of a cross-over interaction between the ig-like domains of gcsf-r and gcsf. the ig-like domain cross-over structure necessary for gcsf-r activation is consistent with previously reported thermodynamic and mutational analyses. SIGNOR-144743 0.766 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 0.248 PIK3C2A protein O00443 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 23119004 t gcesareni Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3). SIGNOR-199367 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 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. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity. SIGNOR-252809 0.2 NHLH2 protein Q02577 UNIPROT ASCL1 protein P50553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21573214 f miannu Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. SIGNOR-254823 0.241 PPP3CB protein P16298 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-248378 0.614 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 0.8 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 0.7 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191304 0.8 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 0.2 CSNK2A1 protein P68400 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates activity phosphorylation Thr143 EFKGEDLtEEEDGGI -1 9405642 t llicata Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90 SIGNOR-250865 0.343 SYNE2 protein Q8WXH0 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-263283 0.534 Matrine chemical CHEBI:6700 ChEBI OPRK1 protein P41145 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-194316 0.8 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 0.336 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 0.309 RAD21 protein O60216 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 t lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-263311 0.967 CSNK2A2 protein P19784 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 t llicata Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH). SIGNOR-250980 0.374 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 0.655 IRF4 protein Q15306 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 f IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254501 0.524 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 0.7 SRSF7 protein Q16629 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 t miannu 9g8 and srp20 also enhance the tap rna-binding activity SIGNOR-161338 0.669 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 0.781 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 0.487 CTSG protein P08311 UNIPROT SERPIND1 protein P05546 UNIPROT down-regulates activity cleavage Val458 QATTVTTvGFMPLST -1 2318847 t miannu Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC. SIGNOR-256509 0.444 SERPINC1 protein P01008 UNIPROT F10 protein P00742 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264138 0.877 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 0.2 migalastat chemical CHEBI:135923 ChEBI GLA protein P06280 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003676 10866822 t Federica 1-Deoxygalactonojirimycin was the most potent inhibitor of a-Gal A with an IC50 value of 0.04mm. SIGNOR-261076 0.8 MAPK3 protein P27361 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL -1 32482868 t lperfetto ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation SIGNOR-236250 0.707 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr702 FGMSRDVySTDYYRV 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc SIGNOR-250205 0.2 UVB radiation stimulus SIGNOR-ST17 SIGNOR calciol smallmolecule CHEBI:28940 ChEBI up-regulates quantity chemical modification 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270562 0.7 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 0.522 NR4A3 protein Q92570 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 30455429 f miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. SIGNOR-259398 0.7 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 0.565 Integrator complex complex SIGNOR-C265 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 26220997 f lperfetto  In vivo knockdown and rescue experiments confirmed that the 3′ end processing of HVS pre-miRNAs also depends on Integrator activity. Interaction between Integrator and HVS primary miRNA (pri-miRNA) substrates that contain only the miRNA 3′ box was confirmed by coimmunoprecipitation and an in situ proximity ligation assay (PLA) SIGNOR-261475 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP153 protein P49790 UNIPROT unknown phosphorylation 9606 19767751 t inferred from 70% family members llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-270159 0.2 SMAD3 protein P84022 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 23032366 f lperfetto PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. SIGNOR-245441 0.563 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 0.777 SOD1 protein P00441 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates activity binding 10090 BTO:0001279 20797535 t P00441:p.Gly38Arg (mutation causing interaction) Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. SIGNOR-262798 0.425 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004408 29606353 t Gianni Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. SIGNOR-269066 0.446 PPP2CA protein P67775 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 16596250 t Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. SIGNOR-248617 0.432 topotecan chemical CHEBI:63632 ChEBI TOP1MT protein Q969P6 UNIPROT down-regulates activity chemical inhibition 9606 11166732 t miannu Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. SIGNOR-259318 0.8 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 0.337 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 0.847 MYC protein P01106 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization 9606 26049753 f Overexpression of c-MYC resulted in SIRT1 deubiquitination, whereas c-MYC knockdown led to decrease in SIRT1 protein stability and expression. SIGNOR-261558 0.572 DAXX protein Q9UER7 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 9743501 t gcesareni Daxx was found to activate the jnk kinase kinase ask1, and overexpression of a kinase-deficient ask1 mutant inhibited fas- and daxx-induced apoptosis and jnk activation. SIGNOR-60164 0.841 SLC9A1 protein P19634 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-265600 0.8 TRIB3 protein Q96RU7 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity binding 9606 BTO:0000007 BTO:0000759 12791994 t llicata TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. SIGNOR-252644 0.619 CHMP2B protein Q9UQN3 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-265530 0.683 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 2846551 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-23757 0.247 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14592841 f This data confirms that PU.1 is a downstream target of activated C/EBPα and is suppressed in FLT3/ITD-expressing cells as a result of C/EBPα suppression. SIGNOR-261530 0.622 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 0.538 TP53 protein P04637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 EXOC5 protein O00471 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-270788 0.941 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 0.2 dutasteride chemical CHEBI:521033 ChEBI ESR2 protein Q92731 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-191445 0.8 VCP protein P55072 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-261372 0.884 alvocidib chemical CHEBI:47344 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191532 0.8 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 0.339 SIRT5 protein Q9NXA8 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity catalytic activity 9606 27113762 t Monia Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. SIGNOR-261211 0.278 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 0.756 NFE2L2 protein Q16236 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18629308 f miannu When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. SIGNOR-254645 0.2 resiquimod chemical CHEBI:36706 ChEBI TLR8 protein Q9NR97 UNIPROT up-regulates activity chemical activation 9606 15661881 t miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. SIGNOR-259247 0.8 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 t Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266907 0.8 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 0.395 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206130 0.8 PTPN6 protein P29350 UNIPROT JAK1 protein P23458 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 t gcesareni We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation. SIGNOR-119197 0.646 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-250917 0.307 INVS protein Q9Y283 UNIPROT DVL1 protein O14640 UNIPROT down-regulates ubiquitination 9606 15852005 t gcesareni Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation SIGNOR-135766 0.641 TLE5 protein Q08117 UNIPROT SIX3 protein O95343 UNIPROT down-regulates activity binding -1 12441302 t lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes SIGNOR-234586 0.2 ETS1 protein P14921 UNIPROT SLC26A3 protein P40879 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 7935445 f miannu Ets-1 activates the DRA promoter in B cells. SIGNOR-254085 0.2 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser652 LERPFRPsVTSVGHV -1 24548923 t miannu Akt phosphorylates S637 and S645 in the linker region of Carma1  SIGNOR-276620 0.522 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 0.765 PTPRO protein Q16827 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 24708807 t miannu In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling. SIGNOR-277062 0.376 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 0.45 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 0.572 CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 16161044 t gcesareni In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm. SIGNOR-140412 0.871 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207645 0.8 CAMK2A protein Q9UQM7 UNIPROT LRRC7 protein Q96NW7 UNIPROT unknown phosphorylation Ser1439 IQTKGQRsMDGYPEQ 11160423 t llicata In contrast, phosphorylation of densin-180 by CaMKII at serine-1397 only slightly decreases its affinity for CaMKII. The specific interaction of densin-180 with holoenzymes of CaMKII containing only alpha-subunit and the increased affinity of CaMKII for densin-180 after autophosphorylation suggest that densin-180 may be involved in localization of activated CaMKII synthesized in dendrites. SIGNOR-250634 0.427 PRL protein P01236 UNIPROT KRT14 protein P02533 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-251902 0.281 CUDC-907 chemical CID:54575456 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191206 0.8 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 0.262 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268289 0.735 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 27023846 f miannu Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate production in eukaryotic cells. SIGNOR-261487 0.7 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51203 0.699 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT down-regulates activity phosphorylation Ser51 DQEWESPsPPKPTVF 9606 20537536 t miannu A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. SIGNOR-259812 0.395 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT unknown phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation. SIGNOR-252577 0.4 GSK3B protein P49841 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity phosphorylation Ser78 PMGPHSMsVPTTPTL 9606 BTO:0000007 29137318 t miannu GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.  SIGNOR-277371 0.275 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9753485 t Crohn's Disease gcesareni SIGNOR-251703 0.8 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2110 FGLARDIyKNDYYRK 9606 17416557 t gcesareni In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products. SIGNOR-154199 0.374 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH10 protein Q9Y6N8 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-265828 0.8 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 0.576 EP300 protein Q09472 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-81053 0.681 LDHA protein P00338 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000164 9192621 f The lactate dehydrogenase-A gene (LDH-A), whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, was identified as a c-Myc-responsive gene. SIGNOR-259370 0.7 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCA protein P17252 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190344 0.8 BTF3 protein P20290 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 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-253950 0.2 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 16829981 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 SIGNOR-147856 0.591 KLF2 protein Q9Y5W3 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19661484 f miannu Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. SIGNOR-254543 0.429 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 8940173 t lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor SIGNOR-45122 0.582 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 t lperfetto these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493. SIGNOR-226628 0.619 PIAS1 protein O75925 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation. SIGNOR-162156 0.494 Org 27569 chemical CID:44828492 PUBCHEM CNR1 protein P21554 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195097 0.8 GSK690693 chemical CHEBI:90677 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193006 0.8 RND1 protein Q92730 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor SIGNOR-152811 0.321 PCDHA3 protein Q9Y5H8 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-265668 0.2 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 0.7 heme smallmolecule CHEBI:30413 ChEBI FBXO22 protein Q8NEZ5 UNIPROT up-regulates activity chemical activation 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-259332 0.8 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 0.8 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. SIGNOR-75997 0.344 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 0.2 PRKACA protein P17612 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t miannu Ser-42 can be phosphorylated by either protein kinase A or protein kinase C SIGNOR-249999 0.329 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1363 HVQSVLLtPQDEFFI 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276264 0.353 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120252 0.316 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr207 DIDQTATyEDIVTLR -1 9531288 t CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b SIGNOR-251155 0.672 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 0.7 LEPR protein P48357 UNIPROT SH2B1 protein Q9NRF2 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-253077 0.333 PIK3R1 protein P27986 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242640 0.851 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 0.78 PRKCH protein P24723 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-251634 0.2 CYSLTR1 protein Q9Y271 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257225 0.405 nocodazole chemical CHEBI:34892 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194838 0.8 OGDHL protein Q9ULD0 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 t miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-267833 0.655 MRPL36 protein Q9P0J6 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-262361 0.724 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 0.274 PRKCZ protein Q05513 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 14657655 t gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. SIGNOR-119889 0.597 AP-2 complex complex SIGNOR-C245 SIGNOR 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-260663 0.601 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 10542134 t miannu Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR.  SIGNOR-272934 0.76 MAPK8 protein P45983 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 14967141 t gcesareni Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l) SIGNOR-121940 0.686 PRKCA protein P17252 UNIPROT GPM6A protein P51674 UNIPROT up-regulates activity phosphorylation Thr10 ENMEEGQtQKGCFEC 10116 BTO:0001009 12359212 t miannu In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells. SIGNOR-263163 0.324 FABP3 protein P05413 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-264457 0.7 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 BTO:0000459 20921139 t lperfetto we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2. SIGNOR-168252 0.786 TBX2 protein Q13207 UNIPROT MYOD1 protein P15172 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-251560 0.31 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 0.7 lurasidone chemical CHEBI:70735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10030 20404009 t Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. SIGNOR-259465 0.8 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg424 KNMEDLHrHIFWEPD -1 12372819 t miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. SIGNOR-256515 0.313 ABL1 protein P00519 UNIPROT APBB1 protein O00213 UNIPROT up-regulates phosphorylation Tyr547 VQKFQVYyLGNVPVA 9606 15031292 t lperfetto The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain. SIGNOR-123476 0.415 CSNK1E protein P49674 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 BTO:0000782 3133391 t gcesareni Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex. SIGNOR-24443 0.288 SLC9A1 protein P19634 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-265591 0.8 MOG protein Q16653 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 33290135 f SimoneGraziosi Myelin oligodendrocyte glycoprotein (MOG) is a nervous system protein expressed by oligodendrocytes to constitute the myelin sheath. SIGNOR-269232 0.7 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250880 0.329 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline chemical CHEBI:94782 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190919 0.8 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 0.281 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 0.291 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 0.723 HIF1A protein Q16665 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 8955077 f inferred from family member miannu we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1. SIGNOR-270229 0.336 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 0.7 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 0.703 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A3-B3 complex SIGNOR-C140 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-243967 0.8 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 0.7 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr286 VEGDAAEtPPRPRTP 10090 BTO:0000944 11684694 t llicata Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. | suggesting that Thr286 in MEK1 is a site of cdk5/p35 phosphorylation that inhibits MEK1 activity. SIGNOR-250653 0.5 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr402 PEQSKRStMVGTPYW -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-250230 0.2 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT 9606 18550549 t gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. SIGNOR-178884 0.272 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 0.278 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271;BTO:0000876 11742995 t lperfetto The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription SIGNOR-217201 0.408 AKT1 protein P31749 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  SIGNOR-274067 0.2 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 0.8 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 t gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. SIGNOR-156356 0.837 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8887554 t lperfetto We show that mapkap kinase-2 phosphorylates creb at ser133 in vitro. SIGNOR-44384 0.691 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 0.246 PGM1 protein P36871 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267930 0.8 CAMK2A protein Q9UQM7 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000938 BTO:0000142 20643921 t gcesareni Nmda-dependent internalization of gabab receptors requires activation of ca2+/calmodulin-dependent protein kinase ii (camkii), which associates with gabab receptors in vivo and phosphorylates serine 867 (s867) in the intracellular c terminus of the gabab1 subunit. SIGNOR-166846 0.237 AXIN1 protein O15169 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates binding 9606 BTO:0000007 12878610 t gcesareni Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation. SIGNOR-104003 0.42 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser630 VLSSTFLsPQCSPQH 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251248 0.397 RAD50 protein Q92878 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 17713585 t fstefani To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-157478 0.2 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 0.2 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser36 PSEGRQPsPSPSPTE 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). SIGNOR-124240 0.359 RET protein P07949 UNIPROT AFAP1L2 protein Q8N4X5 UNIPROT up-regulates activity phosphorylation Tyr54 SSSSDEEyIYMNKVT 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-263192 0.33 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 0.525 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 0.28 glutamine smallmolecule CHEBI:28300 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268009 0.7 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 0.461 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 0.418 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 0.2 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263216 0.765 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 0.73 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 0.2 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252976 0.517 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 0.29 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 0.541 NR4A3 protein Q92570 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 30455429 t miannu NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis. SIGNOR-259399 0.2 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 0.56 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 0.2 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 0.2 GRIA3 protein P42263 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-264613 0.7 HOXB1 protein P14653 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 t Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively SIGNOR-261633 0.274 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser337 DPRGRLRsADSENAL 9606 12761205 t lperfetto Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 2 SIGNOR-101216 0.2 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 0.714 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 0.784 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 0.391 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 0.943 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 0.7 NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.482 CH5132799 chemical CID:49784945 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190949 0.8 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 0.2 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1222 PAFDNLYyWDQDPPE -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251130 0.2 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 0.881 LRRC4 protein Q9HBW1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264054 0.353 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 0.2 silodosin chemical CHEBI:135929 ChEBI ADRA1A protein P35348 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206914 0.8 CDK2 protein P24941 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 t llicata Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity. SIGNOR-116508 0.374 EGR1 protein P18146 UNIPROT COL4A1 protein P02462 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-251917 0.2 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 0.2 CEBPA protein P49715 UNIPROT FTO protein Q9C0B1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 24877091 f lperfetto CCAAT/Enhancer-Binding Protein 𝛼 Is a Crucial SIGNOR-261805 0.346 CSNK2B protein P67870 UNIPROT USO1 protein O60763 UNIPROT up-regulates activity phosphorylation Ser942 EEEDELEsGDQEDED -1 10931861 t llicata Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae SIGNOR-251082 0.335 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 0.2 APOA1 protein P02647 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates 9606 20642861 t miannu ApoA-I increases cholesterol release in mature human adipocytes. SIGNOR-252104 0.8 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 0.674 GNG2 protein P59768 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-251108 0.466 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity binding -1 10497253 t lperfetto Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7. SIGNOR-70947 0.67 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CITED1 protein Q99966 UNIPROT up-regulates binding 9606 9660950 t lperfetto The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276. SIGNOR-216331 0.2 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 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-251820 0.64 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 0.355 CREB1 protein P16220 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 17668895 f gcesareni Phosphorylation of creb by msk has been linked to the of nur77, nor1 and c-fos downstream of mapkin various cell types SIGNOR-157151 0.662 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 0.272 PRDM14 protein Q9GZV8 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 f SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. SIGNOR-269261 0.7 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 19706603 t gcesareni Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18. SIGNOR-187761 0.476 FGF14 protein Q92915 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 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-253417 0.282 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 BTO:0000007 14983059 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-122978 0.408 AKT1 protein P31749 UNIPROT 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-84963 0.765 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 0.294 GLS2 protein Q9UI32 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266911 0.8 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT up-regulates activity phosphorylation Ser205 HPFLRRNsGC -1 11336675 t miannu AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations.  SIGNOR-250324 0.32 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr742 HMVQTNHyQVSGYPG 9606 BTO:0000195 17289681 t The effect has been demonstrated using P34152-3 gcesareni We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress. SIGNOR-152967 0.649 SKP2 protein Q13309 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates ubiquitination 9606 15998794 t gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. SIGNOR-138490 0.772 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 0.8 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 0.795 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. SIGNOR-253000 0.681 BRCA1-B complex complex SIGNOR-C298 SIGNOR G1/S_transition_checkpoint phenotype SIGNOR-PH147 SIGNOR up-regulates 25400280 f 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-263225 0.7 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 0.671 PP1 proteinfamily SIGNOR-PF54 SIGNOR NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 t lperfetto Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1 SIGNOR-264667 0.2 MICU2 protein Q8IYU8 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270860 0.658 POT1/ACD complex SIGNOR-C64 SIGNOR 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-263318 0.859 RPRD1B protein Q9NQG5 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004953 30518842 t lperfetto These results indicated that CREPT regulates the Cyclin B1 expression via directly targeting its promoter region during transcription. SIGNOR-265500 0.2 CDC14B protein O60729 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT unknown dephosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates. SIGNOR-248338 0.406 KMT2A protein Q03164 UNIPROT KAT8 protein Q9H7Z6 UNIPROT up-regulates binding 9606 15960975 t miannu Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome SIGNOR-138245 0.488 ADAMTS13 protein Q76LX8 UNIPROT VWF protein P04275 UNIPROT down-regulates activity cleavage 9606 23020315 t miannu Proteolytic degradation of VWF by ADAMTS-13 downregulates the proinflammatory potential of VWF.  SIGNOR-251966 0.599 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other t The effect has been demonstrated using Q07817-1 gcesareni SIGNOR-207462 0.8 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 0.339 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates 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-66749 0.746 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 0.741 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT down-regulates activity phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. SIGNOR-249187 0.386 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr387 VYFTYDPySEEDPDE -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251377 0.644 PRKAA1 protein Q13131 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr101 IVLNKGKtIFRFSAT 9606 BTO:0002181 30759345 t miannu AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5. SIGNOR-277432 0.2 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 0.943 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 0.351 MAX protein P61244 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 8425218 t esanto In vivo transactivation assays suggest that myc-max and mad-max complexes have opposing functions in transcription and that max plays a central role in this network of transcription factors SIGNOR-39137 0.743 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 0.671 SMUG1 protein Q53HV7 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-275712 0.7 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 17429065 t lperfetto Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. SIGNOR-232113 0.2 BCORL1 protein Q5H9F3 UNIPROT HDAC7 protein Q8WUI4 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-259114 0.48 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 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 f miannu The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m. SIGNOR-254658 0.359 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 0.7 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194922 0.8 VASP protein P50552 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-268390 0.7 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Thr2159 NGATEQRtSSKESSP 9606 BTO:0000938 17088250 t miannu We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment. SIGNOR-150471 0.334 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 0.428 RAG2 protein P55895 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-198245 0.267 MTOR protein P42345 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates activity phosphorylation Ser550 KITSLSSsLDTSLDF 9606 BTO:0001938 26139536 t miannu MTOR phosphorylates UVRAG at serine 550 and serine 571 SIGNOR-276920 0.408 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 0.8 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164671 0.2 BCLAF1 protein Q9NYF8 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17938203 f Luana These results demonstrate that Btf positively regulates TP53 expression through CPE-TP53. SIGNOR-261568 0.413 ACD protein Q96AP0 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-263328 0.2 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its 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-78681 0.272 Caspase 3 complex complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT up-regulates activity cleavage Asp76 MTDSDCRdNAPRTIF 9606 BTO:0001370 9334240 t lperfetto Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.|Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. SIGNOR-256379 0.483 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 0.739 CSNK2A2 protein P19784 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser263 GEDTLSDsDDEDDEE -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-251015 0.367 SRC protein P12931 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates activity phosphorylation Tyr99 REMLEGFyEEISKGR 10090 24331927 t miannu Our results show that only Src can efficiently phosphorylate FHOD1 at Y99 to enable the downstream activation by ROCK. SIGNOR-276612 0.306 HOXA9 protein P31269 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.62 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 0.635 GSK3A protein P49840 UNIPROT GYS1 protein P13807 UNIPROT down-regulates phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t gcesareni 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-118927 0.411 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Msk (mitogen- and stress-activated kinase) 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf- b isoform p65 and stat (signal transducer and activator of transcription) 1 and 3 SIGNOR-166664 0.385 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 0.548 GSK3B protein P49841 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser129 QKRREILsRRPSYRK 10116 12162494 t GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant SIGNOR-251233 0.691 ERBB2 protein P04626 UNIPROT MSI1 protein O43347 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20443831 f gcesareni We investigated the possibilities that erbb2 may regulate downstream mediators of notch1 signaling to induce musashi1 (which enhances notch1 signaling). SIGNOR-165195 0.266 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT up-regulates quantity by stabilization 9606 32644488 f lperfetto VWF plays a crucial role in hemostasis through platelet adhesion facilitation and coagulation factor VIII stabilization SIGNOR-261865 0.789 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 0.2 PRKCD protein Q05655 UNIPROT NCF4 protein Q15080 UNIPROT up-regulates activity phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000738 9804763 t lperfetto P40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process. SIGNOR-249012 0.355 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259434 0.2 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT up-regulates phosphorylation Tyr342 RLIKEDVyLSHDHNI 9606 BTO:0000150 12121988 t miannu Autophosphorylation increases enzyme activity of wild-type brk but not of a y342a mutant form of brk. SIGNOR-90604 0.2 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 0.8 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 0.2 ID1 protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-255942 0.334 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21908610 t gcesareni In addition, although mutation of ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of dusp9/mkp-4, phospho-mimetic (ser-58 to glu) substitution inhibits both the interaction of dusp9/mkp-4 with erk2 and p38? In vivo and its ability to dephosphorylate and inactivate these map kinases. SIGNOR-176586 0.699 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 0.773 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function SIGNOR-266980 0.4 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 0.321 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 0.7 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 0.686 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 0.793 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr435 ARPVKGAyREHPYGR 9606 16179349 t lperfetto We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. SIGNOR-249293 0.748 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. SIGNOR-84827 0.923 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(His) smallmolecule CHEBI:29178 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-269488 0.8 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 0.789 GNB1 protein P62873 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-145119 0.564 SFPQ protein P23246 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 9756848 t miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i SIGNOR-60563 0.372 monoisononyl phthalate chemical CHEBI:132593 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268780 0.8 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-175288 0.91 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser294 RAANLWPsPLMIKRS 9606 BTO:0000150 23390529 t lperfetto The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha SIGNOR-200867 0.477 PRKCA protein P17252 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0000007 20110267 t llicata Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation. SIGNOR-163667 0.29 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 0.868 bisphenol A chemical CHEBI:33216 ChEBI TPO protein P07202 UNIPROT down-regulates activity chemical inhibition -1 17379648 t miannu Half-maximal inhibition of TPO by BPA and F21388 occurred at 174 and 37.5 mol/liter in the guaiacol assay. SIGNOR-268786 0.8 PIM proteinfamily SIGNOR-PF34 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. SIGNOR-259409 0.2 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 0.404 PROK2 protein Q9HC23 UNIPROT PROKR2 protein Q8NFJ6 UNIPROT up-regulates binding 9606 12024206 t gcesareni We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2) SIGNOR-87919 0.665 CHEK2 protein O96017 UNIPROT PSME3 protein P61289 UNIPROT up-regulates activity phosphorylation Ser247 EKIKRPRsSNAETLY 9606 BTO:0001938 25361978 t miannu REGγ interacts with DBC1 and is phosphorylated by Chk2. SIGNOR-273611 0.349 ABL1 protein P00519 UNIPROT PRDX2 protein P32119 UNIPROT down-regulates activity phosphorylation Tyr193 NVDDSKEyFSKHN -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276280 0.284 nepicastat chemical CHEBI:139334 ChEBI DBH protein P09172 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194625 0.8 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262503 0.2 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-200030 0.8 RRAGC protein Q9HB90 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 t lperfetto Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor. SIGNOR-217547 0.699 HASPIN protein Q8TF76 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr4 tKQTARKS 9606 20705812 t miannu Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph. SIGNOR-275428 0.2 SKI protein P12755 UNIPROT SMAD3 protein P84022 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-232123 0.728 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 0.7 NCOA1 protein Q15788 UNIPROT STAT5A protein P42229 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-100258 0.405 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 0.519 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 0.7 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser750 QTEEEEHsCLEQAS 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-66352 0.2 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 0.606 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH24 protein Q86UP0 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-265840 0.8 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10085134 t Amphiregulin is an autocrine growth factor gcesareni The epidermal growth factor receptor (EGFR) mediates the actions of a family of bioactive peptides that include epidermal growth factor (EGF) and amphiregulin (AR) SIGNOR-65576 0.771 (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 0.8 TERF2 protein Q15554 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 BTO:0000567 15383534 t lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. SIGNOR-263317 0.808 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 t gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-142297 0.29 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159438 0.26 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 10090 22848740 t When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form. SIGNOR-255756 0.411 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1452 LPSSSPRsPSGLRPR 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-274102 0.405 CDK5 protein Q00535 UNIPROT APP protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS 10116 BTO:0000938 10936190 t llicata In vitro, active cyclin-dependent kinase 5 (Cdk5) phosphorylated the cytoplasmic domain of APP at Thr(668). Treatment of mature neurons with an antisense oligonucleotide to Cdk5 suppressed Cdk5 expression and significantly diminished the level of phosphorylated APP. The expression of APP was unaffected in antisense-treated neurons. These results indicate that in neurons APP is phosphorylated by Cdk5, and that this may play a role in its localization. SIGNOR-250651 0.565 DUSP5 protein Q16690 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10224087 t gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-67358 0.76 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 0.269 SRSF11 protein Q05519 UNIPROT APOE protein P02649 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 10090 31269452 t miannu We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. SIGNOR-269671 0.2 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 0.39 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193549 0.8 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 0.654 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 0.268 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH15 protein P55291 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-265832 0.8 PD173074 chemical CHEBI:63448 ChEBI FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205728 0.8 RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20975042 t svumbaca In addition, we show that the transcription of IL1B depends on a positively acting p65/c-Rel/ikbb complex SIGNOR-256237 0.555 DPF2 protein Q92785 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity binding 9606 24332853 t miannu The interaction between RUNX1 and DPF2 is dependent on the RUNX1 methylation status SIGNOR-261966 0.2 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t lperfetto Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity SIGNOR-236506 0.2 HSD17B11 protein Q8NBQ5 UNIPROT androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363 30943210 t lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone SIGNOR-268660 0.8 NTRK1 protein P04629 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12446789 t gcesareni Grit translocation was regulated by receptor stimulation SIGNOR-95809 0.602 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 0.868 JMJD1C protein Q15652 UNIPROT H3C1 protein P68431 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-265171 0.2 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 0.451 TIMM22 protein Q9Y584 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-267706 0.678 PRKACA protein P17612 UNIPROT CDK16 protein Q00536 UNIPROT down-regulates phosphorylation Ser153 SRRLRRVsLSEIGFG 9606 BTO:0000142 22184064 t llicata Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site. SIGNOR-191623 0.314 ECM stimulus SIGNOR-ST20 SIGNOR A5/b1 integrin complex SIGNOR-C163 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-259046 0.7 SP7 protein Q8TDD2 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 f miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. SIGNOR-254219 0.365 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser531 RTHSAGTsPTITHQK -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-251297 0.654 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 0.593 TP53 protein P04637 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15377670 f miannu We isolated a p53-regulated gene named ndrg1 (n-myc down-regulated gene 1). Its expression is induced by dna damage in a p53-dependent fashion. SIGNOR-129183 0.529 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001938 24300895 f These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity. SIGNOR-253063 0.2 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser18 SPADDSLsNSEEEPD 9606 21559372 t llicata Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist. SIGNOR-173668 0.2 SRC protein P12931 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates activity phosphorylation Tyr2217 ELQDSRVyVSSL 9606 BTO:0000007 17942635 t miannu Cotransfection of human embryonic kidney (HEK)-293 cells with hCa(v)1.2b and c-Src resulted in tyrosine phosphorylation of the calcium channel, which was prevented by nitration of tyrosine residues by peroxynitrite. Whole cell calcium currents were reduced by 58 + 5% by the Src kinase inhibitor PP2 and 64 + 6% by peroxynitrite.  SIGNOR-276081 0.443 SRC protein P12931 UNIPROT CDCP1 protein Q9H5V8 UNIPROT unknown phosphorylation Tyr734 KDNDSHVyAVIEDTM 9606 14739293 t lperfetto Phosphorylation of gp140 and p80 are mediated by Src family kinases at multiple Tyr residues including Tyr(734). SIGNOR-246457 0.529 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 0.25 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 0.356 NDUFB2 protein O95178 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262165 0.785 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates activity phosphorylation Ser196 RSLEVWGsQEALEEA 9606 30327428 t ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215. SIGNOR-258985 0.492 SMAD7 protein O15105 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates binding 9606 17384642 t gcesareni The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling. SIGNOR-153920 0.382 IGFBP5 protein P24593 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0000165 18762576 f These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop. SIGNOR-255940 0.7 CBLB protein Q13191 UNIPROT KIT protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 t miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. SIGNOR-260105 0.328 CDK19 protein Q9BWU1 UNIPROT PAK1 protein Q13153 UNIPROT unknown phosphorylation Ser174 TPAVPPVsEDEDDDD 9606 19520772 t llicata Here, we identified p21 activated kinase 1 (pak1) as a new cdk11(p58) substrate and we mapped a new phosphorylation site of ser174 on pak1 SIGNOR-185000 0.332 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Thr540 KRLSRSVtMRKSQRS -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276330 0.2 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 0.327 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8557118 t gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-243199 0.365 HAP1 protein P54257 UNIPROT KIF5C protein O60282 UNIPROT up-regulates activity binding 9606 31757889 t miannu HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro SIGNOR-264062 0.402 MARCHF1 protein Q8TCQ1 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-271410 0.2 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr643 EELNKRQtQKDLEHA 9606 17396146 t gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. SIGNOR-154171 0.42 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 t fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes SIGNOR-168562 0.8 spiperone chemical CHEBI:9233 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 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-258894 0.8 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser544 RSVTMRKsQRSSKGS -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276331 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 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-53784 0.2 PRKCA protein P17252 UNIPROT GRIN2A protein Q12879 UNIPROT unknown phosphorylation Ser1416 ASYCSRDsRGHNDVY 10116 11104776 t lperfetto PKC-dependent phosphorylation of NR2A(Ser(1416)) as a key mechanism in inhibiting alphaCaMKII-binding and promoting dissociation of alphaCaMKII.NR2A complex. SIGNOR-249065 0.505 YAP1 protein P46937 UNIPROT TUBB protein P07437 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276571 0.2 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 0.705 C1QA protein P02745 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 t lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). SIGNOR-263390 0.646 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-260087 0.317 RXRA protein P19793 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16668 0.682 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Thr355 NFSSSPStPVGSPQG 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161544 0.2 FYN protein P06241 UNIPROT NOX4 protein Q9NPH5 UNIPROT down-regulates activity phosphorylation Tyr566 LSNQNNSyGTRFEYN -1 27525436 t miannu We found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. SIGNOR-277273 0.271 KDM4B protein O94953 UNIPROT TP53I3 protein Q53FA7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 f miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. SIGNOR-263731 0.2 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 CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206133 0.8 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1009 LDTSSVLyTAVQPNE 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-18575 0.2 SPI1 protein P17947 UNIPROT EGR2 protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 f miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation SIGNOR-256040 0.371 DYNLL2 protein Q96FJ2 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 t gcesareni The beclin 1 vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1 interacting protein ambra1 and dynein light chains 1/2 SIGNOR-168289 0.463 ATM protein Q13315 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates phosphorylation Ser274 MILIQDGsQNTNVDK 9606 21329876 t lperfetto The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing SIGNOR-172123 0.423 UMPS protein P11172 UNIPROT UMP smallmolecule CHEBI:16695 ChEBI up-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267440 0.8 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005907 25026211 t miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. SIGNOR-272230 0.2 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser8 MPLNRTLsMSSLPGL -1 2117608 t miannu Phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase has been shown to enhance subsequent phosphorylation by casein kinase I . phosphorylation at Ser7 is required for modification of Ser10 by casein kinase I. SIGNOR-249988 0.508 TCF3 protein P15923 UNIPROT CR2 protein P20023 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11739509 f miannu We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny. SIGNOR-255387 0.281 CCKBR protein P32239 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-257412 0.509 PAX3 protein P23760 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 f gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181621 0.479 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 0.2 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277228 0.464 SMOC1 protein Q9H4F8 UNIPROT COL1A1 protein P02452 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-260402 0.2 AMPK complex SIGNOR-C15 SIGNOR RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 19815529 t lperfetto 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-216592 0.283 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 19574738 t gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c SIGNOR-186621 0.858 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A4 protein P31645 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-257943 0.8 UBR5 protein O95071 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys115 YKYRPRRkTKTLMKK 9606 BTO:0002428 30894683 t miannu We identified UBR5 as a major ubiquitin E3 ligase that induces SOX2 degradation through ubiquitinating SOX2 at lysine 115. SIGNOR-277446 0.256 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 0.2 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236318 0.704 CHMP6 protein Q96FZ7 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-265526 0.673 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 0.439 TGFB1 protein P01137 UNIPROT CDK4 protein P11802 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000763 8402878 f gcesareni Here we show that tgf beta 1 induces suppression of cdk4 synthesis in g1 in mink lung epithelial cells. SIGNOR-39045 0.282 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser5 sESFTMAS 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187396 0.962 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 0.49 PDGFRA protein P16234 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 t miannu Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production. SIGNOR-28176 0.65 RIMBP3C protein A6NJZ7 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264362 0.265 HCRTR1 protein O43613 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-256876 0.25 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR LATS1 protein O95835 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005907 25026211 t miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. SIGNOR-272229 0.361 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 9606 9681662 t Simone Vumbaca Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues. SIGNOR-261091 0.8 GATA1 protein P15976 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-256051 0.502 TNFRSF17 protein Q02223 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79498 0.2 BS-181 hydrochloride chemical CID:49867928 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190783 0.8 HIF1A protein Q16665 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity transcriptional regulation 9606 8387214 t Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. SIGNOR-256592 0.773 NANOG protein Q9H9S0 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16840789 t Luana We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.  SIGNOR-266080 0.2 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 0.522 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 0.923 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 0.7 FZR1 protein Q9UM11 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity binding 9606 19822757 t lperfetto Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity SIGNOR-265081 0.761 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000150 22418700 t gcesareni Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members. SIGNOR-259442 0.8 INTS8 protein Q75QN2 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261472 0.743 MAPK3 protein P27361 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 12792650 t lperfetto Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk SIGNOR-101548 0.535 TFAP4 protein Q01664 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 19505873 f miannu AP-4 Mediates E-box-dependent Complex Formation for Transcriptional Repression of HDM2 SIGNOR-226596 0.2 MAF protein O75444 UNIPROT ETS1 protein P14921 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-56808 0.425 CHEK1 protein O14757 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity phosphorylation Ser296 GFSKHIQsNLDFSPV 8355 15707391 t lperfetto This suggests that Ser296 is probably one of the sites autophosphorylated when Chk1 is fully activated [21], despite the sequence surrounding Ser296 (FSKHIQS296NL) being only weakly related to the optimal Chk1-recognition motif (M/I/L/V)-X-(R/K)-X-X-(S/T), where (S/T) is the phosphorylated residue SIGNOR-219240 0.2 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser285 QRVPSYDsFDSEDYP 9606 BTO:0000782 12475968 t lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition SIGNOR-96342 0.309 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Thr1362 YEEHIPYtHMNGGKK -1 8463287 t lperfetto Therefore, the present study directly identifies threonine 1336 in the HIR as a phosphorylation site for insulin and PMA. SIGNOR-248933 0.348 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 0.7 TAF5 protein Q15542 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-263929 0.897 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 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-257738 0.8 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 0.395 MORF4L1 protein Q9UBU8 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-269299 0.757 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 0.647 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 0.289 PRKAA2 protein P54646 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 SIGNOR-C15 21459323 t gcesareni Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372 SIGNOR-173031 0.328 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 0.6 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 0.2 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 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9606191 f lperfetto Here we report the identification of smad3/smad4 binding sequences, termed caga boxes, within the promoter of the human pai-1 gene. SIGNOR-57776 0.591 AXIN1 protein O15169 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10829020 t gcesareni We found that in contrast to axin, dvl2 activation of jnk does not require mekk1. SIGNOR-77591 0.515 MAP3K3 protein Q99759 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5. SIGNOR-104637 0.72 CDH12 protein P55289 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-265852 0.509 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 0.2 ACSS1 protein Q9NUB1 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271830 0.8 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 0.328 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 0.506 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser695 MSQPSTAsNSLPEPA 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-251281 0.2 dapagliflozin chemical CHEBI:85078 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191289 0.8 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10807576 f Nuclear p53 amattioni Expression of noxa was dependent on p53. Noxa represent a mediator of p53-dependent apoptosis. SIGNOR-76152 0.702 agomelatine chemical CHEBI:134990 ChEBI HTR2C protein P28335 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189474 0.8 MAPK3 protein P27361 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-188147 0.391 NR5A1 protein Q13285 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254869 0.472 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 0.2 TFCP2 protein Q12800 UNIPROT TF protein P02787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20796026 f miannu Ectopic expression of CP2 led to increased transferrin expression at both the mRNA and protein levels, whereas knockdown of CP2 down-regulated transferrin mRNA and protein expression. SIGNOR-255429 0.2 MAP3K1 protein Q13233 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 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-244881 0.661 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 0.7 BMS-265246 chemical CID:5329775 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190431 0.8 N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide chemical CHEBI:91360 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates activity chemical inhibition -1 16162000 t miannu A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β. SIGNOR-262222 0.8 p38 proteinfamily SIGNOR-PF16 SIGNOR CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser491 GSCCTIMsPGEMEKH 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276363 0.2 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Thr336 GDDEASAtVSKTETS -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248969 0.439 CRBN protein Q96SW2 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 t gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors SIGNOR-234805 0.788 FOXJ3 protein Q9UPW0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 19914232 t Luana Foxj3 transcriptionally activates Mef2c and regulates adult skeletal muscle fiber type identity. SIGNOR-261606 0.317 RORB protein Q92753 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-268003 0.478 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser169 VLRNITNsQAPDGRR 9606 15908796 t lperfetto We demonstrate that cdc25b is phosphorylated in vitro by peg3 on serine 169this phosphorylated form of cdc25b accumulates during mitosis, and is localized to the centrosomes SIGNOR-137378 0.533 PPP1CA protein P62136 UNIPROT NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 t gcesareni Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1 SIGNOR-152949 0.374 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 0.587 WNT7B protein P56706 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 t gcesareni Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling. SIGNOR-137931 0.67 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys20 AEEALPKkTGGPQGS 9606 23552949 t gcesareni Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine SIGNOR-201662 0.314 luminespib chemical CHEBI:83656 ChEBI HSP90AA1 protein P07900 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190038 0.8 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr313 SSEPVGIyQGFEKKT 9534 BTO:0000298 11381116 t The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). SIGNOR-251384 0.526 Sitagliptin phosphate monohydrate chemical CID:11591741 PUBCHEM DPP4 protein P27487 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206923 0.8 SRC protein P12931 UNIPROT MMP3 protein P08254 UNIPROT up-regulates activity 23967200 f C-Src-induced STAT3 activation regulates MMP3 levels SIGNOR-251109 0.34 DAGLB protein Q8NCG7 UNIPROT episterol ester smallmolecule CHEBI:52393 ChEBI up-regulates quantity chemical modification 9606 26787883 t miannu Diacylglycerol lipases (DAGLŒ± and DAGLŒ≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. SIGNOR-264265 0.8 SOX9 protein P48436 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression 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-255190 0.373 MEN1 protein O00255 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 11526476 t miannu Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner. SIGNOR-110067 0.462 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 0.371 MK-8245 chemical CID:24988881 PUBCHEM SCD protein O00767 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194420 0.8 SRC protein P12931 UNIPROT GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 t inferred from family member gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. SIGNOR-270262 0.27 IFNG protein P01579 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 f lperfetto IFN-_ induces socs1 gene expression through an inducible factor SIGNOR-236809 0.556 CAMK1 protein Q14012 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 10090 23707388 t Monia We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization; SIGNOR-261195 0.305 A10/b1 integrin complex SIGNOR-C167 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269016 0.7 RPS11 protein P62280 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-262441 0.889 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249344 0.739 58131-57-0 chemical CID:42640 PUBCHEM MDM4 protein O15151 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194856 0.8 SMAD7 protein O15105 UNIPROT STRAP protein Q9Y3F4 UNIPROT up-regulates binding 9606 10757800 t gcesareni Strap recruits smad7 to the activated type i receptor and forms a complex SIGNOR-76771 0.61 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 0.59 RASSF6 protein Q6ZTQ3 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 22830020 t gcesareni When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway. SIGNOR-198463 0.658 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 0.2 MAVS protein Q7Z434 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates relocalization 9606 16406812 t gcesareni Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif SIGNOR-143572 0.587 GSK3B protein P49841 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Thr153 EALLGQAtPPGTGQF 9606 21873430 t miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. SIGNOR-276355 0.286 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 0.8 SRC protein P12931 UNIPROT GLRB protein P48167 UNIPROT up-regulates phosphorylation Tyr435 RDFELSNyDCYGKPI 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 t gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. SIGNOR-115705 0.27 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 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-255833 0.2 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 0.7 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Thr27 WAKGRREtYLCYVVK 9606 18417471 t llicata We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43 SIGNOR-178248 0.324 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 0.96 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 0.496 JDP2 protein Q8WYK2 UNIPROT JUN protein P05412 UNIPROT down-regulates activity binding 9606 18671972 t miannu JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE). SIGNOR-226398 0.607 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-252793 0.2 IGF1R protein P08069 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr250 DMGHLKYyLAPKIED -1 28924044 t miannu In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. SIGNOR-277252 0.2 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1716180 t lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. SIGNOR-21320 0.485 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 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-131568 0.701 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 0.31 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI AFP protein P02771 UNIPROT down-regulates quantity by repression 9606 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 0.8 MAPK1 protein P28482 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-249436 0.812 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity deacetylation 9606 BTO:0001103 22395773 t lperfetto SIRT1 controls the acetylation of FOXO transcription factors, which are important regulators of lipid and glucose metabolism as well as stress response. On the other hand, SIRT1 can also stimulate the gluconeogenic transcriptional program by deacetylating and activating FOXO1. SIGNOR-253509 0.81 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 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 t llicata 14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642. SIGNOR-148342 0.2 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates quantity binding 9606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265441 0.2 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 0.8 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 0.917 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 0.385 AKT3 protein Q9Y243 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. SIGNOR-201129 0.261 Dinaciclib chemical CID:46926350 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191322 0.8 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 0.455 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 0.396 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 0.7 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 0.2 RET protein P07949 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 8183561 t gcesareni We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret. SIGNOR-36902 0.656 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 0.678 ZNF148 protein Q9UQR1 UNIPROT SOX18 protein P35713 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18496767 f miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells SIGNOR-254821 0.258 DNMT1 protein P26358 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18413740 f lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation SIGNOR-254108 0.2 PPP2CA protein P67775 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT down-regulates activity dephosphorylation 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-273793 0.2 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 0.8 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251031 0.434 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252822 0.911 AKT1 protein P31749 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr299 QSRKRLAtSSASSQS 9606 BTO:0002181 32123010 t miannu Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation. SIGNOR-277515 0.2 LRIG3 protein Q6UXM1 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates 9606 23723069 f miannu Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors. SIGNOR-202180 0.305 RAC1 protein P63000 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 21712438 f gcesareni Hypertonicity activates p38 via a rac1-osm-mekk3-mkk3-p38 pathway. SIGNOR-174602 0.536 MYCT1 protein Q8N699 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-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-261728 0.7 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates activity phosphorylation Ser299 EGEDDRDsANGEDDS 9606 15687492 t gcesareni In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. SIGNOR-133536 0.354 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 0.2 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 11971190 t lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation SIGNOR-117575 0.2 EIF6 protein P56537 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates quantity binding 9606 10085284 t lperfetto The beta4 integrin interactor p27(BBP/eIF6) is an essential nuclear matrix protein involved in 60S ribosomal subunit assembly. SIGNOR-269151 0.492 SOX6 protein P35712 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-251808 0.311 MID1 protein O15344 UNIPROT HMG20B protein Q9P0W2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28760657 t miannu The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35. MID1 is implicated in BRAF35 ubiquitination promoting atypical poly-ubiquitination via K6-, K27- and K29-linkages. We found that MID1 depletion alters BRAF35 localization in these structures and increases BRAF35 stability affecting its cytoplasmic abundance SIGNOR-272317 0.244 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Ser102 KDGNGYIsAAELRHV -1 26675311 t miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. SIGNOR-266354 0.422 alogliptin chemical CHEBI:72323 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition -1 22475866 t Luana Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization. SIGNOR-258333 0.8 BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-87109 0.545 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser3 sKRAKAKT 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-192792 0.278 CRTC2 protein Q53ET0 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity binding 9606 26652733 t We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). SIGNOR-256101 0.294 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 0.464 GRIK3 protein Q13003 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268274 0.8 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182971 0.743 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 0.765 PMF1 protein Q6P1K2 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-265192 0.835 Serum stimulus SIGNOR-ST3 SIGNOR PRKAA2 protein P54646 UNIPROT down-regulates 9606 19584320 f miannu Ampk is activated under conditions of low energy charge and typically inhibits anabolic reactions and promotes catabolism SIGNOR-186644 0.7 CREB1 protein P16220 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 Brivanib alaninate chemical CID:11154925 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190726 0.8 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 0.2 YES1 protein P07947 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 t miannu SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1. SIGNOR-276858 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000562 23457334 t lperfetto Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids. SIGNOR-192260 0.2 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 0.76 VAMP3 protein Q15836 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-253082 0.726 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 0.2 NXPH1 protein P58417 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 t gcesareni Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1 SIGNOR-62699 0.548 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 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/cdk3 SIGNOR-217256 0.715 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity phosphorylation Ser60 DNTAGCTsAGPHFNP 4932 24647101 t ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes. SIGNOR-262794 0.376 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 0.2 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 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-269097 0.8 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249685 0.411 Clinofibrate chemical CHEBI:31412 ChEBI HMGCR protein P04035 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191085 0.8 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 8626452 t fstefani Here we characterize a new map kinase phosphatase, mkp-2, that is induced in human peripheral blood t cells with phorbol 12-myristate 13-acetate and is expressed in a variety of nonhematopoietic tissues as well. 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-40926 0.762 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 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-188969 0.2 SRC protein P12931 UNIPROT KRT19 protein P08727 UNIPROT unknown phosphorylation Tyr391 LEGQEDHyNNLSASK 9606 21049038 t llicata Human k19 tyrosine 391 is phosphorylated, potentially by src kinase, and is the first well-defined tyrosine phosphorylation site of any keratin protein. SIGNOR-169273 0.289 AKT proteinfamily SIGNOR-PF24 SIGNOR BEX1 protein Q9HBH7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser102 KLREKQLsHSLRAVS 10116 BTO:0001009 16498402 t miannu Phosphorylation of Bex1 in Ser105 by the serine–threonine kinase AKT stabilizes Bex1 and protects it from proteasomal degradation SIGNOR-262614 0.2 BZW2 protein Q9Y6E2 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity binding 9606 31643092 t miannu BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro SIGNOR-261220 0.253 AKT proteinfamily SIGNOR-PF24 SIGNOR 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 of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252836 0.911 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. SIGNOR-251473 0.2 MAPK14 protein Q16539 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser310 LYNFMCNsSCVGGMN -1 30301786 t miannu P38α phosphorylates and destabilizes p63. SIGNOR-277414  0.307 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 0.277 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t gcesareni Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l. SIGNOR-153604 0.446 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 0.703 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 0.642 TYK2 protein P29597 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates activity phosphorylation Tyr693 TERGDKGyVPSVFIP 9606 16324152 t miannu IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693. SIGNOR-279303 0.656 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1191 GELSRSPsPFTHTHL 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-187599 0.497 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000664 10411939 t irozzo Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes. SIGNOR-256071 0.577 IRF5 protein Q13568 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249562 0.7 REL protein Q04864 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR form complex binding 9606 BTO:0000671 9056676 t miannu Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel. SIGNOR-46945 0.676 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 0.448 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 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-256275 0.487 ITGB1BP1 protein O14713 UNIPROT A9/b1 integrin complex SIGNOR-C166 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-257646 0.732 N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide chemical CHEBI:94175 ChEBI SHH protein Q15465 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 21679342 t gcesareni More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch. SIGNOR-174429 0.8 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 0.527 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 0.422 WDCP protein Q9H6R7 UNIPROT KIF2A protein O00139 UNIPROT up-regulates activity binding 9606 BTO:0000007 30297404 t miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11.  SIGNOR-273732 0.2 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr442 KILEEVRyIANRFRC 9606 BTO:0000938 16251431 t lperfetto Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinasesmutant alpha7 nachrs lacking cytoplasmic loop tyrosine residues because of alanine replacement of tyr-386 and tyr-442 were more active than wild-type receptorsexpression of active src reduced _7 nachr activity SIGNOR-141311 0.2 MCM complex SIGNOR-C268 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19946136 f 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-261678 0.7 MT-ND5 protein P03915 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262148 0.772 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser712 EEEESDSsETEKEDD -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276249 0.2 IRF4 protein Q15306 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 f However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. SIGNOR-254284 0.298 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 11175253 t amattioni Activated tbid results in an allosteric activation of bak SIGNOR-105210 0.822 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 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-202042 0.732 EIF3_complex complex SIGNOR-C401 SIGNOR Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR 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-269154 0.638 AKT1 protein P31749 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 t lperfetto Akt phosphorylated sek1 on serine 78. SIGNOR-236494 0.594 LHB protein P01229 UNIPROT LHCGR protein P22888 UNIPROT up-regulates binding 9606 10446903 t gcesareni Hcg is a heterodimeric glycoprotein hormone, consisting of a common? -subunit and a hormone-specific ?-Subunit (2). It binds to the lh receptor (lhr). SIGNOR-70028 0.684 YY2 protein O15391 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 15087442 t Luana YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter. SIGNOR-266213 0.572 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 0.282 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 0.8 DRD4 protein P21917 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264995 0.461 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 14976264 t lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-122408 0.911 LSM-1988 chemical CHEBI:92015 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189394 0.8 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189356 0.8 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 0.642 SCF-FBW7 complex SIGNOR-C135 SIGNOR FOXM1 protein Q08050 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26912724 t miannu GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. SIGNOR-277209 0.304 CSNK2A1 protein P68400 UNIPROT AIP protein O00170 UNIPROT unknown phosphorylation Ser43 FHYRTLHsDDEGTVL 9534 12361709 t llicata Protein kinase CK2 (CK2) was identified as the 45-kDa kinase from COS 1 cell or liver extracts that was responsible for phosphorylation of serine 43 in the XAP2 peptide 39-57. Loss of phosphorylation at any or all of the serine residues did not significantly affect the ability of XAP2-FLAG to bind to the murine AhR in rabbit reticulocyte lysate or Hsp90 in COS-1 cells. SIGNOR-250824 0.307 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser20 KSSDFLEsAELDSGG -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276160 0.2 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 0.2 IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26178471 t lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (Œ±-KG) SIGNOR-261828 0.8 FHIT protein P49789 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000551 15313915 f miannu We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein. SIGNOR-127915 0.473 ABL1 protein P00519 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT down-regulates phosphorylation Tyr1073 PSGQPTPyATTQLIQ 9606 10892742 t gcesareni Abl functions to antagonize robo signaling both abl and ena can directly bind to robo's cytoplasmic domain. SIGNOR-78993 0.606 RAD51C protein O43502 UNIPROT XRCC3 protein O43542 UNIPROT up-regulates activity relocalization 9606 23438602 f lperfetto It is likely that the recruitment of RAD51C to the sites of DNA lesions can promote XRCC3 phosphorylation and activate the DNA damage response pathway(s) in the S and G2 phases.  SIGNOR-263260 0.667 TP73 protein O15350 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 17700533 f miannu Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. SIGNOR-255473 0.7 NUP93 protein Q8N1F7 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262081 0.717 RBM15 protein Q96T37 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR form complex binding 9606 17001072 t miannu Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression. SIGNOR-149883 0.489 PRKACA protein P17612 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 9660950 t llicata The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka). SIGNOR-58972 0.516 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser90 QHVRSHSsPASLQLG 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276522 0.262 NR3C1 protein P04150 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001372 9430225 f In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX SIGNOR-253295 0.413 BAK1 protein Q16611 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-118908 0.295 CDK8 protein P49336 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-273178 0.552 CASP3 protein P42574 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-66860 0.7 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1. SIGNOR-166661 0.615 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni Transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells. SIGNOR-52005 0.817 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 0.718 TRAF7 protein Q6Q0C0 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates binding 9606 15001576 t miannu Traf7 specifically interacts with and activates mekk3. SIGNOR-123221 0.484 SP1 protein P08047 UNIPROT DHCR24 protein Q15392 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22431021 f miannu activation of Sp1 by oxidative stress is involved in the promotion of expression of DHCR24 by HCV. SIGNOR-255200 0.2 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 0.595 KAT2B protein Q92831 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269611 0.2 BCL2L11 protein O43521 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133832 0.783 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM3B protein Q7LBC6 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-273471 0.8 NDC80 protein O14777 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 t lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits SIGNOR-265188 0.967 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 0.441 CSTF2 protein P33240 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 t lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  SIGNOR-268366 0.929 ATF4 protein P18848 UNIPROT WARS1 protein P23381 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269429 0.2 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 10090 BTO:0002572;BTO:0000801 21232017 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-235407 0.895 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 0.703 ERBB3 protein P21860 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146864 0.521 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-227911 0.712 TRIM65 protein Q6PJ69 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003172 31332286 t miannu Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation SIGNOR-272256 0.2 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 t gcesareni Furthermore, we show that prak activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by prak following activation of p38 mapk by ras plays an important role in ras-induced senescence and tumor suppression. SIGNOR-152850 0.76 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 0.415 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 0.692 GSK3B protein P49841 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser33 LPENNVLsPLPSQAM 9606 11483158 t Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity. SIGNOR-251258 0.728 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 0.85 KLF14 protein Q8TD94 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression transcriptional regulation 19088080 f lperfetto Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. SIGNOR-271696 0.2 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 0.8 SRGAP3 protein O43295 UNIPROT RAC2 protein P15153 UNIPROT down-regulates 9606 12447388 f miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95921 0.552 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249681 0.517 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 17190791 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1). SIGNOR-151671 0.446 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 t lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer SIGNOR-263208 0.842 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates dephosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 t lperfetto Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively. SIGNOR-184604 0.367 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 0.7 SPI1 protein P17947 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 f However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. SIGNOR-254286 0.328 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003323 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-263237 0.711 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 0.704 PRKACA protein P17612 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2347 TTCCRRSsNVSYKYS 9606 8318012 t lperfetto Pka phosphorylates the cytoplasmic mpr 300 domain at ser20 and at a non-identified site, SIGNOR-37839 0.2 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 0.718 Av/b3 integrin complex SIGNOR-C177 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269026 0.7 PPP3CA protein Q08209 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176379 0.566 STAT3 protein P40763 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30029643 f Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway. SIGNOR-256257 0.7 E2F1 protein Q01094 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253854 0.683 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation 9606 7478566 t gcesareni For example, inactivation of sos through phosphorylation by the downstream mapk SIGNOR-26338 0.636 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 0.464 SLX4 protein Q8IY92 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates binding 9606 24726326 t lperfetto Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair. SIGNOR-217652 0.82 ANXA3 protein P12429 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR 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-262210 0.2 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 9606 11163214 t Manara PSTPIP1 was phosphorylated by ABL1, and growth factor–induced PSTPIP1 phosphorylation was diminished in Abl null fibroblasts. SIGNOR-260809 0.597 GATA1 protein P15976 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251804 0.378 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-154255 0.477 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser622 ILSTAMLsLGSGISQ 9534 BTO:0000298 11865049 t llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  SIGNOR-250815 0.74 PP1 proteinfamily SIGNOR-PF54 SIGNOR CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 t lperfetto Protein phosphatase-1 activates cdk9 by dephosphorylating ser175 SIGNOR-264671 0.2 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206838 0.8 CH5132799 chemical CID:49784945 PUBCHEM PIK3C2B protein O00750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190940 0.8 ATM protein Q13315 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000887 18534819 f lperfetto The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. SIGNOR-244392 0.448 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 0.589 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267255 0.8 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 0.316 DUSP6 protein Q16828 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-103146 0.904 Cy3-bifunctional dye zwitterion chemical CHEBI:37990 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-257859 0.8 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 0.784 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 18498746 t gcesareni Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf). SIGNOR-178686 0.759 HSPA8 protein P11142 UNIPROT RNF5 protein Q99942 UNIPROT up-regulates activity 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-271493 0.387 APBA1 protein Q02410 UNIPROT CASK protein O14936 UNIPROT up-regulates activity binding 9534 11036064 t miannu Interaction with Munc18 increases Mint1 binding to CASK. SIGNOR-264041 0.851 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 f We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα. SIGNOR-256117 0.46 BMP2 protein P12643 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 9606 22298955 f gcesareni Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation SIGNOR-195564 0.698 MAPK3 protein P27361 UNIPROT 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-253012 0.576 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates quantity binding 9606 BTO:0000007;BTO:0000567 14523016 t amattioni Smac3, a novel Smac/DIABLO splicing variant, accelerates XIAP auto-ubiquitination and destruction SIGNOR-118411 0.914 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 0.2 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 0.308 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 0.2 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 0.476 PDPK1 protein O15530 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Thr423 PEQSKRStMVGTPYW 9534 BTO:0000298 10995762 t miannu P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1. SIGNOR-250267 0.357 MAPK8 protein P45983 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 12351702 t gcesareni Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription. SIGNOR-93558 0.638 SLC25A12 protein O75746 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265154 0.8 RBL2 protein Q08999 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity transcriptional regulation 10090 10801445 f gcesareni Furthermore, muscle cells overexpressing p130 had reduced levels of the muscle-promoting factor MyoD. In addition, p130 repressed the transactivation capacity of MyoD, an effect abolished by co-transfection of pRb SIGNOR-241943 0.371 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 0.2 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 0.651 CALM3 protein P0DP25 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 t inferred from 70% of family members miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-269891 0.641 STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 10347215 f lperfetto The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages. SIGNOR-249547 0.7 2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol chemical CHEBI:64064 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana The affinity measurements (log KD values of −5.73, −9.26 and −6.33 for β1, β2 and β3, respectively), show that salmeterol has high affinity for the β2-adrenoceptor.  SIGNOR-257852 0.8 SMO protein Q99835 UNIPROT GNAT2 protein P19087 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-148534 0.262 PRDM16 protein Q9HAZ2 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 t _activating its transcriptional function fspada Prdm16 stimulates brown adipogenesis by binding to ppar-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function SIGNOR-180298 0.469 NOTCH2 protein Q04721 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 9528794 t gcesareni In an effort to identify processes that regulate e47, and potentially b-cell development, we found that activated notch1 and notch2 effectively inhibit e47 activity. SIGNOR-56222 0.273 calciol smallmolecule CHEBI:28940 ChEBI vitamin D smallmolecule CHEBI:27300 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-270564 0.8 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 0.8 EIF4E protein P06730 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex SIGNOR-236806 0.7 STK3 protein Q13188 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Thr180 DTMAKRNtVIGTPFW 9606 BTO:0000150 20231902 t gcesareni Consistent with previous studies, sts alone induces mst2 cleavage and autophosphorylation of thr180, an indicator of mst2 activation, as well as apoptosis. SIGNOR-164310 0.2 PFKL protein P17858 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-266468 0.8 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. SIGNOR-156868 0.704 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 0.7 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 0.401 GNB1 protein P62873 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 t apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit SIGNOR-255004 0.94 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr73 ADQTPTPtRFLKNCE 9606 15105425 t gcesareni Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level. SIGNOR-124334 0.371 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG 9606 SIGNOR-C14 11460167 t lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. SIGNOR-109490 0.755 PPM1B protein O75688 UNIPROT DYRK1A protein Q13627 UNIPROT down-regulates activity dephosphorylation Ser258 NTNFRGVsLNLTRKF 9606 33380426 t miannu In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity.|We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity. SIGNOR-277108 0.236 AVPR2 protein P30518 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256754 0.589 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 0.2 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205746 0.8 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 0.396 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 0.69 MTMR1 protein Q13613 UNIPROT 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 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-269805 0.8 INTS5 protein Q6P9B9 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-261465 0.905 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 11892915 t gcesareni Vx-745 was reported to be active against several isotypes of p38 mapk, including p38alpha, p38beta and p38gamma SIGNOR-115782 0.8 RAB8A protein P61006 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 f miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110 SIGNOR-252148 0.7 PTPN1 protein P18031 UNIPROT EPOR protein P19235 UNIPROT down-regulates activity dephosphorylation 9606 14527337 t lperfetto In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling. SIGNOR-276994 0.459 GIT1 protein Q9Y2X7 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity binding 9606 BTO:0000599 23325602 t miannu We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. SIGNOR-261245 0.391 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys37 TPSTCGVkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275879 0.2 alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267935 0.8 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr166 LYCDPRGtLRKGTLG -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273491 0.267 IL23A protein Q9NPF7 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 12023369 t gcesareni Like il-12, il-23 binds to the il-12r subunit il-12rbeta1. SIGNOR-87739 0.645 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 0.7 IL17A protein Q16552 UNIPROT IL17RA protein Q96F46 UNIPROT up-regulates binding 9606 BTO:0000782 9367539 t gcesareni Binding studies suggest that recombinant hil-17 binds to the hil-17r with low affinity. Monoclonal antibodies (mabs) generated against the hil-17r were able to block the il-17-induced production of cytokine from human foreskin fibroblast (hff) cells. SIGNOR-53249 0.924 KIFC1 protein Q9BW19 UNIPROT Cell_migration phenotype SIGNOR-PH38 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-266115 0.7 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 0.748 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 f miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. SIGNOR-253376 0.7 BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.636 TNFSF11 protein O14788 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 f miannu Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation SIGNOR-253044 0.7 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 0.884 IRAK4 protein Q9NWZ3 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-251329 0.687 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA1 protein P42261 UNIPROT up-regulates activity chemical activation 10090 15115814 t lperfetto AMPA glutamate receptor subunit (GluR1) SIGNOR-261432 0.8 CREB1 protein P16220 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 SIGNOR-268145 0.25 IFNW1 protein P05000 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-105982 0.758 KLF15 protein Q9UIH9 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-253817 0.272 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 0.2 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation Ser25 PELLVVGsRPELGRW 9606 BTO:0000007 21728993 t miannu In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser(25) as the residue involved in this modification. We also show that Ser(25) is phosphorylated both in vitro and in vivo by AMPK.  SIGNOR-276338 0.351 nintedanib chemical CHEBI:85164 ChEBI PDGFRA protein P16234 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-257805 0.8 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0000567 11070080 t gcesareni P300 acetylates and activates the tumor suppressor p53 after dna damage. SIGNOR-84074 0.912 SATB1 protein Q01826 UNIPROT CD52 protein P31358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255131 0.2 PFDN4 protein Q9NQP4 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-270933 0.942 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 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-204550 0.2 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000165 19319192 t miannu We previously showed that the level of MAFbx protein increased in skeletal muscle during aging and/or food deprivation. Immunoprecipitation of the SCFMAFbx complexes from mouse atrophic muscles exhibited ubiquitination activity by using MyoD as substrate. Food deprivation and oxidative stress–induced atrophy increase polyubiquitination by the SCFMAFbx pathway and degradation of MyoD by the proteasome SIGNOR-271802 0.56 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 0.221 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 0.324 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 0.2 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Ser43 QTPSKPAsADGHRGP 9606 BTO:0002181 33388549 t miannu Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation SIGNOR-277543 0.383 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 0.759 PAK2 protein Q13177 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, SIGNOR-159768 0.512 AGTR1 protein P30556 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260233 0.7 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 0.57 PKI-402 chemical CID:44187953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252654 0.8 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser507 TDLCFLNsPIFKQKK 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-156882 0.2 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 0.661 MTA1 protein Q13330 UNIPROT MTA1/DJ1 complex complex SIGNOR-C123 SIGNOR form complex binding 9606 21368136 t 1 miannu We found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. SIGNOR-239739 0.328 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr224 DSNSKKIyGSQPNFN -1 12573241 t Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. SIGNOR-251332 0.334 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 0.413 HASPIN protein Q8TF76 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 BTO:0000567 24413556 t miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. SIGNOR-275420 0.2 HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 f Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1 SIGNOR-253058 0.7 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 0.2 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 0.291 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Thr519 EDPYAGStDENTDSE 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-251051 0.46 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 22298955 t gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation SIGNOR-195606 0.458 YWHAQ protein P27348 UNIPROT PRKD1 protein Q15139 UNIPROT down-regulates -1 10092600 f lperfetto 14-3-3tau strongly down-regulates pkcmu kinase activity in vitro SIGNOR-65951 0.327 LTK protein P29376 UNIPROT CBL protein P22681 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85. SIGNOR-49528 0.369 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 0.7 valsartan chemical CHEBI:9927 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 8577935 t miannu The binding characteristics of the angiotensin AT1 receptor antagonist valsartan were investigated in different animal species and tissues. SIGNOR-258489 0.8 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr202 HDHTGFLtEYVATRW 1712480 t lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| SIGNOR-249471 0.2 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 0.396 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 0.7 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 0.2 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 0.435 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 0.2 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 0.574 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 0.517 WZ4002 chemical CHEBI:61400 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207827 0.8 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 0.433 LPCAT4 protein Q643R3 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272770 0.8 BIRC2 protein Q13490 UNIPROT CASP2 protein P42575 UNIPROT down-regulates binding 9606 16701639 t gcesareni However, among hiap1, hiap2 and xiap, only hiap2 binds and inhibits caspase-2. SIGNOR-146738 0.498 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 16085715 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-139477 0.642 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser83 PRRSPRIsFFLEKEN -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276119 0.629 CASP1 protein P29466 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256400 0.79 NR0B2 protein Q15466 UNIPROT HNF4A protein P41235 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10594021 f gcesareni Here we show that shp inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (hnf-4) and the retinoid x receptor (rxr) by at least two mechanisms shp also competes with coactivators for binding to ligand-activated rxr, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of shp-mediated repression. SIGNOR-73032 0.429 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 t gcesareni We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner. SIGNOR-195549 0.423 BLM protein P54132 UNIPROT UIMC1 protein Q96RL1 UNIPROT up-regulates activity binding 9606 BTO:0001938 23708797 t miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .  SIGNOR-272116 0.329 ENOBOSARM chemical CID:11326715 PUBCHEM AR protein P10275 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-195892 0.8 PHKG2 protein P15735 UNIPROT PYGM protein P11217 UNIPROT up-regulates activity phosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267400 0.55 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 t gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation. SIGNOR-146122 0.524 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243983 0.2 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 12181444 t gcesareni In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme. SIGNOR-91477 0.558 RNF139 protein Q8WU17 UNIPROT SREBF2 protein Q12772 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  SIGNOR-271958 0.477 mTORC2 complex SIGNOR-C2 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser436 INQSTLPsQQNRFPD 9606 BTO:0002036 34343821 t miannu Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. SIGNOR-277569 0.281 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 0.737 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 0.699 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser692 GQLMSQPsTASNSLP 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251280 0.2 ERK1/2 proteinfamily SIGNOR-PF1 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-270145 0.2 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser771 SASSTLGsPENEEHI 9606 SIGNOR-C3 21757713 t llicata Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation. SIGNOR-174870 0.352 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 0.8 CDC42BPA protein Q5VT25 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW BTO:0000567 11340065 t llicata Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment. SIGNOR-250721 0.404 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser298 EKLAKHEsQQDYSKG 9606 20363754 t lperfetto Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding SIGNOR-164756 0.421 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 10090 26260587 t lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-249546 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0005248 8758906 t irozzo We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. SIGNOR-255999 0.2 IRAK4 protein Q9NWZ3 UNIPROT PELI2 protein Q9HAT8 UNIPROT up-regulates phosphorylation 9606 12860405 t gcesareni Pellino2 is one of the firstsubstrates identified for irak1 andirak4. SIGNOR-103717 0.638 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 0.489 nilutamide chemical CHEBI:7573 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194649 0.8 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0000142 1411546 t gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-19244 0.742 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser139 YFLGSSFsPVRCGGP 9606 BTO:0000007 23051732 t lperfetto In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues.  SIGNOR-267470 0.545 PTPN13 protein Q12923 UNIPROT STK25 protein O00506 UNIPROT down-regulates activity dephosphorylation 9606 17657516 t To investigate dephosphorylation of CCM3 by FAP-1, phosphorylated GST-CCM3 was incubated with cdFAP-1, and reactions were analyzed by autoradiography. Again, GST-STK25 phosphorylated GST-CCM3 and possessed autophosphorylation activity. cdFAP-1 of 0.005 U were sufficient to dephosphorylate GST-CCM3 as well as the kinase GST-STK25.|More recently, the Golgi matrix protein GM130 was shown to function as a scaffold protein for STK25 and to activate STK25 through stimulation of autophosphorylation. SIGNOR-248711 0.421 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249677 0.517 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 0.659 NOG protein Q13253 UNIPROT BMP7 protein P18075 UNIPROT down-regulates activity binding -1 12478285 t We report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. SIGNOR-256484 0.852 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-252081 0.2 KAT5 protein Q92993 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000007 21936881 t llicata Tip60 regulates myoblast differentiation by enhancing the transcriptional activity of MyoD via their physical interactions. SIGNOR-237675 0.365 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity phosphorylation Ser467 KASSRRSsFSMEEGD 10090 BTO:0000968 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-255316 0.33 DUSP7 protein Q16829 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150 BTO:0001253 9788880 t gcesareni Pyst2 preferentially dephosphorylates and inactivates p42 map kinase in vitro and in vivo SIGNOR-60871 0.797 MAPK12 protein P53778 UNIPROT NUP62 protein P37198 UNIPROT down-regulates quantity by destabilization phosphorylation Ser272 SGTSTTTsTAATATA 9606 BTO:0000007 30401435 t miannu We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).  SIGNOR-277416 0.2 SNX5 protein Q9Y5X3 UNIPROT DOCK1 protein Q14185 UNIPROT up-regulates activity binding 9606 BTO:0000567 18596235 t miannu SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding. SIGNOR-269441 0.346 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 0.249 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 9687510 t lperfetto Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38,. SIGNOR-59454 0.611 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 0.408 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 0.8 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 10116 7535768 t Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185 SIGNOR-248718 0.762 Histone H2A proteinfamily SIGNOR-PF70 SIGNOR Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-267756 0.2 KIF2C protein Q99661 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272535 0.7 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser1137 EGPTRRLsLPGQLGA 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70718 0.307 ATM protein Q13315 UNIPROT PPM1G protein O15355 UNIPROT up-regulates activity phosphorylation Ser183 GTGEEPGsQGLNGEA -1 26324325 t ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody SIGNOR-255591 0.303 1-[4-Amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-fluoroethanone chemical CID:644243 PUBCHEM RPS6KA2 protein Q15349 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0002135 31505737 t miannu Since p90RSK was activated in the diabetic hearts in mice, we investigated whether FMK (an inhibitor of p90RSK) could protect INS-1 cells (a pancreatic β-cell line) from HG-induced β-cell dysfunction and glucotoxicity. SIGNOR-262231 0.8 SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255838 0.685 RHOA protein P61586 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 11102529 t gcesareni Our results demonstrate that direct stimulation of pld1 in vivo by rhoa SIGNOR-84953 0.697 WWC1 protein Q8IX03 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity 9606 BTO:0000007 20159598 f Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. SIGNOR-261953 0.368 PGD protein P52209 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI up-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-267061 0.8 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 0.2 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 0.2 BUB1 protein O43683 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity relocalization 11402067 t lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity SIGNOR-252017 0.727 SNRNP200 protein O75643 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-270624 0.782 CRHR1 protein P34998 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 22869609 t lperfetto Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3 SIGNOR-268618 0.453 TP53 protein P04637 UNIPROT NR4A3 protein Q92570 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 t miannu We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells. SIGNOR-256200 0.264 RNF170 protein Q96K19 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000567 21610068 t miannu In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound. SIGNOR-271913 0.431 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence. SIGNOR-72458 0.857 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 0.775 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 0.7 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 t gcesareni Enzymatic activity, inhibited; SIGNOR-151771 0.2 phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI CRLS1 protein Q9UJA2 UNIPROT up-regulates activity chemical activation 10090 16678169 t lperfetto The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase. SIGNOR-267029 0.8 ARIH1 protein Q9Y4X5 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 33879767 t miannu We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. SIGNOR-277553 0.2 PIN4 protein Q9Y237 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 9606 BTO:0000567 12860119 f lperfetto Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs  SIGNOR-265755 0.7 TP53 protein P04637 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates 9606 15073170 f gcesareni Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb. SIGNOR-252816 0.357 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation -1 30661366 t miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. SIGNOR-277424 0.2 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 BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other t The effect has been demonstrated using Q07817-1 gcesareni SIGNOR-189153 0.8 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 17157250 t lperfetto Ndpk-b directly binds and activates kca3.1 by phosphorylating histidine 358 in the carboxyl terminus of kca3.1 SIGNOR-151130 0.419 PRKCQ protein Q04759 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR form complex binding 10090 BTO:0000165 20178747 t llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. SIGNOR-238019 0.2 PTEN protein P60484 UNIPROT SP1 protein P08047 UNIPROT down-regulates activity dephosphorylation 9606 21603612 t miannu Moreover, PTEN downregulates p75NTR expression by decreasing DNA-binding activity of Sp1 .|PTEN dephosphorylates the Sp1 transcription factor , the phosphorylation status of which directly impacts its ability to bind to some DNA promoter regions , . SIGNOR-277119 0.421 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell SIGNOR-254301 0.48 TWIST2 protein Q8WVJ9 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 f miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells SIGNOR-255513 0.278 BCKDK protein O14874 UNIPROT BCKDHA protein P12694 UNIPROT down-regulates phosphorylation Ser337 TYRIGHHsTSDDSSA 9606 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000671 3947057 t gcesareni Phosphorylation sites and inactivation of branched-chain alpha-ketoacid dehydrogenase isolated from rat heart, bovine kidney, and rabbit liver, kidney, heart, brain, and skeletal muscle. SIGNOR-25084 0.609 AURKAIP1 protein Q9NWT8 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-261461 0.661 GH1 protein P01241 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15665309 f Luana Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells SIGNOR-261627 0.2 SRGAP3 protein O43295 UNIPROT RAC3 protein P60763 UNIPROT down-regulates 9606 12447388 f miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95964 0.557 DAPK3 protein O43293 UNIPROT RPL13A protein P40429 UNIPROT up-regulates phosphorylation Ser77 PYHFRAPsRIFWRTV 9606 BTO:0000801 18995835 t lperfetto Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro SIGNOR-182117 0.402 COLGALT1 protein Q8NBJ5 UNIPROT ADIPOQ protein Q15848 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 28428430 t We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity. SIGNOR-261149 0.2 TEK protein Q02763 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 18401423 t miannu Tie2-R849W induced STAT1 phosphorylation at Y701 independent of ligand stimulation.|Together, Tie2-R849W induced functional activation of STAT1, leading to increased expression of STAT1-responsive gene like IRF1. SIGNOR-279131 0.301 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu Activated SAPK3 phosphorylates the mitochondrial protein Sab. we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 SIGNOR-250140 0.442 PPP2CA protein P67775 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 17188031 t We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. SIGNOR-248640 0.2 MARK2 protein Q7KZI7 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser873 VDDQKAGsPSRDVGP 9606 22883624 t gcesareni Gab1 brings par1 and par3 into a transient complex, stimulating par3 phosphorylation by par1 SIGNOR-198742 0.493 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 0.395 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 0.87 TNFRSF17 protein Q02223 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates jnk SIGNOR-79492 0.2 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 0.8 SLC25A12 protein O75746 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-265156 0.8 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 0.492 UV stress stimulus SIGNOR-ST7 SIGNOR MAP3K4 protein Q9Y6R4 UNIPROT up-regulates 9606 9305639 f lperfetto Overexpression of a dominant-negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin)[]These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway SIGNOR-226605 0.7 CASP1 protein P29466 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256402 0.703 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 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-227885 0.895 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 0.8 SRC protein P12931 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 t lperfetto Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin|In this study, we also show how pY88 paxillin transduces a signal to activate Akt SIGNOR-263977 0.808 BMPR1B protein O00238 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates phosphorylation 9606 9335504 t inferred from 70% of family members llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. SIGNOR-269846 0.709 GRPEL1 protein Q9HAV7 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267691 0.605 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 0.7 GSK3B protein P49841 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr266 ARHLQENtQSHMRML 9606 BTO:0002181 30806153 t miannu TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. SIGNOR-277438 0.479 ID4 protein P47928 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21531766 f miannu We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3'-untranslated region.  SIGNOR-255180 0.409 Telatinib chemical CID:9808844 PUBCHEM KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207227 0.8 SHC1 protein P29353 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0000782 8995379 t gcesareni T cell activation effects an increase in grap association with p36/38, shc, sos, and dynamin. SIGNOR-45528 0.506 ZM447439 chemical CHEBI:91376 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207920 0.8 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 0.7 oxybutynin chemical CHEBI:7856 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 22243489 t Luana  Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency. SIGNOR-258328 0.8 L-homocysteine zwitterion smallmolecule CHEBI:58199 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-275826 0.8 MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 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 0.781 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 0.7 VHL protein P40337 UNIPROT SPARC protein P09486 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-255603 0.2 NUP62 protein P37198 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-261258 0.94 CD74 protein P04233 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 BTO:0000007;BTO:0000876 19665027 t miannu Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling. SIGNOR-187461 0.531 IL23A protein Q9NPF7 UNIPROT IL23R protein Q5VWK5 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r. SIGNOR-87805 0.861 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166714 0.341 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 0.242 S1PR1 protein P21453 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256713 0.504 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser604 FQSTSVKsPKTVSPP 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-263063 0.2 Caspase 3 complex complex SIGNOR-C221 SIGNOR BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 t miannu We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable. SIGNOR-256432 0.473 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival. SIGNOR-262961 0.481 USP6 protein P35125 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 20418905 f miannu These data confirm that tre17 activates nfkappab in a usp-dependent manner SIGNOR-164949 0.2 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 12270934 t lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-235940 0.75 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC3 protein Q9UN70 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265696 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t irozzo To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity. SIGNOR-256290 0.663 GATOR1 complex SIGNOR-C192 SIGNOR RRAGA protein Q7L523 UNIPROT down-regulates activity gtpase-activating protein -1 23723238 t GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. SIGNOR-253562 0.874 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 0.512 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser266 QYLGSIAsPSVHPAT 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-138932 0.2 CDK2 protein P24941 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr847 FRYIPPNtPENFWEV 9606 19202191 t llicata Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo SIGNOR-183840 0.617 SIK1 protein P57059 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation Ser167 MTPTQPEsFSSGSQD 9606 16817901 t miannu These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities. SIGNOR-147669 0.494 RHOA protein P61586 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Thr567 QGRDKYKtLRQIRQG 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-268429 0.76 MAPK3 protein P27361 UNIPROT SULT4A1 protein Q9BR01 UNIPROT down-regulates phosphorylation Thr11 SEAETPStPGEFESK 9606 BTO:0000938 BTO:0000142 20920535 t gcesareni The phosphorylation of sult4a1 allows interaction with pin1, which then promotes degradation of the sulfotransferase. SIGNOR-168248 0.2 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 0.7 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 0.7 SLC20A2 protein Q08357 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 11009570 t lperfetto SIGNOR-270580 0.8 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 0.594 IL2 protein P60568 UNIPROT IL2RA protein P01589 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-144537 0.927 PPP3CC protein P48454 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-248524 0.404 entinostat chemical CHEBI:132082 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-257904 0.8 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 0.8 CRY1 protein Q16526 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-267975 0.939 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C3 19690328 t lperfetto The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated. SIGNOR-187611 0.849 MTCH1 protein Q9NZJ7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 12377771 f SARA PSAP is an important regulator of apoptosis SIGNOR-260994 0.7 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR TJP2 protein Q9UDY2 UNIPROT up-regulates 9606 21529719 f milica Another junction protein, the tight junction protein ZO-2, binds to YAP/TAZ, facilitating their nuclear translocation. SIGNOR-230703 0.7 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 0.8 KIF5A protein Q12840 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 31753031 t miannu Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions SIGNOR-264065 0.313 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 0.7 CCP110 protein O43303 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 12361598 f miannu Reduction in CP110 Protein Levels or Loss of CP110 Phosphorylation Promotes Centrosome Separation. SIGNOR-265964 0.7 MAP1LC3B protein Q9GZQ8 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe. SIGNOR-191549 0.835 KDM6A protein O15550 UNIPROT ZBTB16 protein Q05516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29736013 t miannu UTX catalytic activity has been reported to upregulate expression of the master transcription factor PLZF and to modulate superenhancer accessibility in invariant natural killer T cells. SIGNOR-260038 0.311 ETS2 protein P15036 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 t miannu We demonstrated that Ets2 is capable of binding to and transactivating the OPN promoter using gel shift and transient transfection assays SIGNOR-259872 0.251 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 0.8 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 0.8 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 0.924 AT9283 chemical CID:11696609 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190014 0.8 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr301 PPGEDSDtDVDDDSR 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-179883 0.346 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCI protein P41743 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-242581 0.8 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 f FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1 gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts SIGNOR-134797 0.307 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 0.653 MAML1 protein Q92585 UNIPROT CCNC protein P24863 UNIPROT up-regulates relocalization 9606 15546612 t gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130709 0.447 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Ser27 SFGFTRTsARRRLAD 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-266299 0.307 STUB1 protein Q9UNE7 UNIPROT IRS4 protein O14654 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 30026872 t miannu IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). SIGNOR-277616 0.2 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257786 0.8 STAT3 protein P40763 UNIPROT KRT17 protein Q04695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21796151 f miannu IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. SIGNOR-255234 0.259 CDK7 protein P50613 UNIPROT PCGF6 protein Q9BYE7 UNIPROT unknown phosphorylation Ser30 LPPPPPVsPPALTPA -1 12167161 t llicata In addition, we find that serine 32 of MBLR is specifically phosphorylated during mitosis, most likely by CDK7, a component of the basal transcriptional machinery. | These results indicate that, at least in vitro, MBLR is a substrate for CDK7 phosphorylation. SIGNOR-250769 0.305 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 0.394 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34665 0.601 PRKCQ protein Q04759 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15364919 t Manara Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). SIGNOR-260906 0.567 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 0.47 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129188 0.2 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser185 KTTQNRYsFYSTCSG -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-273494 0.267 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t llicata By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd SIGNOR-99255 0.339 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 0.447 NEDD4L protein Q96PU5 UNIPROT CLCN5 protein P51795 UNIPROT down-regulates quantity by destabilization ubiquitination 9267 BTO:0003069 15489223 t miannu The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway. SIGNOR-272665 0.292 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Ser2155 GFAEAIHsPQVAGVP 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181014 0.374 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 0.382 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 0.7 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206670 0.8 TBL1Y protein Q9BQ87 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates quantity by destabilization binding 9606 18374649 t Luana TBL1 interacts in vivo with CtBP and promote its proteasomal degradation SIGNOR-260902 0.2 GGCX protein P38435 UNIPROT PROC protein P04070 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265925 0.572 AKT1 protein P31749 UNIPROT LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 t llicata Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis. SIGNOR-252516 0.382 BRD3 protein Q15059 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0003292 28045112 t lperfetto Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3 SIGNOR-262044 0.317 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 0.399 BUB1B protein O60566 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 f gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) SIGNOR-168195 0.7 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 10523516 t gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. SIGNOR-71423 0.784 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. SIGNOR-118542 0.2 SLC27A6 protein Q9Y2P4 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-264467 0.7 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 7993631 t gcesareni We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type. SIGNOR-35626 0.2 CBL protein P22681 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity binding 10090 BTO:0001516 19276253 t Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. SIGNOR-255739 0.436 mTORC1 complex SIGNOR-C3 SIGNOR 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-256063 0.7 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI PTGER3 protein P43115 UNIPROT up-regulates chemical activation 9606 15299086 t gcesareni Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4. SIGNOR-127738 0.8 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser158 FVSHSHIsPIKPTEA 9606 19066288 t llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1 SIGNOR-182761 0.282 MDH2 protein P40926 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-268100 0.8 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-252957 0.717 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 0.825 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t Translocation from Endosome to Lysosome fspada In this study, we demonstrated that ser396 and ser398 are phosphorylated by pkc and, that phosphorylation of ser398 is particularly involved in pmainduced desensitization of the h1r. SIGNOR-66015 0.2 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 t lperfetto We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites. SIGNOR-249406 0.298 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 0.325 DOCK8 protein Q8NF50 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 28028151 t lperfetto Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation.  SIGNOR-268412 0.767 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 0.7 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR4 protein O95977 UNIPROT up-regulates activity chemical activation 9606 10753843 t These results indicate that EDG-6 is a high affinity receptor for SPP, which couples to a G(i/o) protein, resulting in the activation of growth-related signaling pathways SIGNOR-261143 0.8 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 0.2 TNFRSF17 protein Q02223 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates jnk SIGNOR-79489 0.29 HMGB2 protein P26583 UNIPROT POU2F2 protein P09086 UNIPROT up-regulates activity binding 10090 7720710 t 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins SIGNOR-240108 0.32 ATP(4-) smallmolecule CHEBI:30616 ChEBI 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity precursor of 23258413 t lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. SIGNOR-276594 0.8 POMC protein P01189 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity 9606 BTO:0000848 16274845 f miannu Alpha-MSH is an anti-inflammatory peptide which signals by binding to the melanocortin-1 receptor (MC1R) and elevating cyclic AMP in several different cells and tissues. The carboxyl terminal peptides of alpha-MSH (KPV/GKPV) are the smallest minimal sequences that prevent inflammation, but it is not known if they operate via MC1R or cyclic AMP. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity. SIGNOR-252371 0.256 MLH1/PMS2 complex SIGNOR-C59 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 29175432 f MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans SIGNOR-257600 0.7 lurasidone chemical CHEBI:70735 ChEBI ADRA2C protein P18825 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-257837 0.8 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 0.8 POLR2L protein P62875 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266151 0.908 folic acid smallmolecule CHEBI:27470 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 BTO:0000575 19706381 t lperfetto However, since the synthesis of folic acid (FA, pteroylglutamic acid) as a provitamin in 1945, DHFR has taken on another role: reduction of FA to 7,8-DHF (Fig. 1) SIGNOR-268263 0.8 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 0.411 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr77 DPCSLIPtPDKEDDD 9606 14536078 t gcesareni Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380 SIGNOR-118563 0.445 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 0.346 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 0.385 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI1 protein P08151 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0001130 17494766 t gcesareni Gant61 was able to efficiently block gli1 as well as gli2-induced transcription SIGNOR-154753 0.8 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 0.911 PJA1 protein Q8NG27 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates ubiquitination 9606 16247473 t gcesareni The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it. SIGNOR-141216 0.403 ESR1 protein P03372 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-254075 0.3 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT unknown phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 t llicata Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir SIGNOR-183470 0.292 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 0.945 NatA complex SIGNOR-C415 SIGNOR H2AX protein P16104 UNIPROT down-regulates activity acetylation 9606 BTO:0001109 21351257 t miannu The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). SIGNOR-267227 0.2 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 0.8 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 t miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. SIGNOR-256514 0.313 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 0.2 ADAM10 protein O14672 UNIPROT EGF protein P01133 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin SIGNOR-259840 0.566 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 0.8 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 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-273187 0.259 U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 f miannu The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. SIGNOR-263945 0.7 TLX1 protein P31314 UNIPROT PPP2CB protein P62714 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-240722 0.301 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK -1 10734133 t miannu Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant. SIGNOR-75894 0.378 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 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-58481 0.489 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 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-134549 0.722 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194551 0.8 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 0.66 TNKS protein O95271 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000007 19759537 t Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-261249 0.519 SIRT7 protein Q9NRC8 UNIPROT SAR1A protein Q9NR31 UNIPROT up-regulates activity deacetylation 9606 BTO:0002181 28790157 t SARA SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding SIGNOR-260978 0.2 PEX5 protein P50542 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000007 ubiquitination:Lys209 VAKVDDPkLANSEFL 26344566 t Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.  SIGNOR-262793 0.372 IHH protein Q14623 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61311 0.838 TDP2 protein O95551 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 21980489 t miannu TTRAP associates with TRAF6.The TAK1-TTRAP-TRAF6 complex is stabilized by ubiquitylation and recruited to TβRI. SIGNOR-277189 0.378 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK9 protein P45984 UNIPROT down-regulates chemical inhibition 9606 18922779 t BI-78D3 is substrate competitive. gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. SIGNOR-181650 0.8 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 0.325 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser242 MDKRKDPsSVDIKKV -1 10480872 t llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. SIGNOR-250773 0.347 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 0.2 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 0.325 HDAC5 protein Q9UQL6 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 11062529 t gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. SIGNOR-84023 0.706 MAP4K4 protein O95819 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 t miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  SIGNOR-277921 0.2 aliskiren fumarate chemical CHEBI:53777 ChEBI REN protein P00797 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189483 0.8 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR DKK1 protein O94907 UNIPROT up-regulates activity 15229249 f Exposure of the cultures to beta-amyloid peptide (βAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1).  SIGNOR-255482 0.7 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr387 HKKLMFKtEGPDSD 9606 BTO:0001321 15659650 t lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-217861 0.78 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser1018 QVEFRRLsISAESQS 10487978 t miannu Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. Ser1018 within this multiphosphorylation domain is phosphorylated by PKA and is a major site of regulatory phosphorylation in vivo SIGNOR-250026 0.432 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 0.693 MRPL23 protein Q16540 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262370 0.2 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 0.552 GRIA1 protein P42261 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 10090 BTO:0000938 15115814 f lperfetto The targeting and clustering of AMPA and NMDA receptors to synapses in the CNS is essential for efficient excitatory synaptic transmission SIGNOR-261433 0.7 BCORL1 protein Q5H9F3 UNIPROT HDAC5 protein Q9UQL6 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-259113 0.439 TYK2 protein P29597 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity phosphorylation 9606 27782195 t miannu JAK1 and TYK2 will phosphorylate and activate STAT1 and STAT2 respectively, leading to the formation of the ternary interferon-stimulated gene factor 3 (ISGF3) complex, composed of STAT1, STAT2 and interferon regulatory factor 9 (IRF9). SIGNOR-279133 0.789 GATA1 protein P15976 UNIPROT GP1BA protein P07359 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-254191 0.546 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261743 0.405 PIM1 protein P11309 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 17643117 t gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. SIGNOR-265366 0.2 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 0.382 ASPSCR1 protein Q9BZE9 UNIPROT VCPKMT protein Q9H867 UNIPROT up-regulates binding 9606 23349634 t gcesareni In the case of vcp, methylation by mettl21d was stimulated by the addition of the ubx cofactor aspscr1, which we show directly interacts with the methyltransferase. SIGNOR-200572 0.342 TM9SF4 protein Q92544 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 29125601 f miannu In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. Overexpression of TM9SF4 promoted autophagic flux in HEK293 cells. SIGNOR-266704 0.7 TET1 protein Q8NFU7 UNIPROT ZNF382 protein Q96SR6 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-259095 0.2 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 0.637 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 0.2 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Ser695 EERMRMEsRRQATVS -1 23264741 t miannu  Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700.  SIGNOR-276437 0.43 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 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-183640 0.729 ANKS1B protein Q7Z6G8 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 26356309 f miannu AIDA-1 is highly enriched in postsynaptic density (PSD) fractions and is considered a major component of the PSD complex. SIGNOR-264226 0.7 ATP smallmolecule CHEBI:15422 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267837 0.8 4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid chemical CHEBI:64210 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258140 0.8 BAP1 protein Q92560 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 26416890 f lperfetto The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and is Disrupted in Cancer. SIGNOR-241660 0.7 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 0.2 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 0.248 PIM2 protein Q9P1W9 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-250394 0.391 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235471 0.563 acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267107 0.8 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 0.76 PFKFB4 protein Q16877 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity chemical modification 9606 15170386 t Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2 SIGNOR-267264 0.8 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 10636859 t gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. SIGNOR-73967 0.2 PRKCA protein P17252 UNIPROT ITPKA protein P23677 UNIPROT down-regulates activity -1 9374536 t lperfetto In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity). SIGNOR-248991 0.37 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 0.671 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 0.7 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 0.358 RBBP6 protein Q7Z6E9 UNIPROT YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18851979 t miannu RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1 SIGNOR-271773 0.317 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 0.7 zileuton chemical CHEBI:10112 ChEBI ALOX5 protein P09917 UNIPROT down-regulates activity chemical inhibition 10116 1848634 t miannu 5-lipoxygenase inhibitory activity of zileuton. SIGNOR-258363 0.8 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 0.8 MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 t Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. SIGNOR-256079 0.694 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 0.8 SLC16A3 protein O15427 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. SIGNOR-242468 0.7 CNTRL protein Q7Z7A1 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR down-regulates 9606 18694559 f 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-252150 0.7 FUS protein P35637 UNIPROT MATR3 protein P43243 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 27731383 t P35637:p.Pro525Leu (mutation disrupting interaction) Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. SIGNOR-262822 0.486 AV412 chemical CID:11700696 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190050 0.8 DLG3 protein Q92796 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266009 0.647 ERG protein P11308 UNIPROT CXCL8 protein P10145 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001949 19359602 f miannu ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner. SIGNOR-253912 0.2 UVB radiation stimulus SIGNOR-ST17 SIGNOR IL1A protein P01583 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-252384 0.7 PLK1 protein P53350 UNIPROT MRE11 protein P49959 UNIPROT down-regulates activity phosphorylation Ser649 EVIEVDEsDVEEDIF 9606 BTO:0001938 28512243 t miannu Plk1 phosphorylates Mre11 at S649.Mre11 phosphorylation at S649/S688 inhibits its binding to dsDNA and antagonizes the ATM signaling. SIGNOR-265943 0.2 RNF19A protein Q9NV58 UNIPROT CASR protein P41180 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16513638 t miannu Coexpression with dorfin decreased the amount of total CaR protein and increased CaR ubiquitination, whereas a dominant negative fragment of dorfin had opposite effects. dorfin-mediated proteasomal degradation of immature CaR occurs from the endoplasmic reticulum. Because endogenous CaR in Madin-Darby canine kidney cells is also subject to degradation from the endoplasmic reticulum, dorfin-mediated ubiquitination may contribute to a general mechanism for CaR quality control during biosynthesis. SIGNOR-271456 0.381 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 0.2 MCHR2 protein Q969V1 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-257390 0.435 RELA protein Q04206 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 SIGNOR-C13 18174238 t gcesareni Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment SIGNOR-160330 0.719 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 14556242 t lperfetto In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. SIGNOR-118615 0.942 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 0.7 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 0.734 CSNK2A1 protein P68400 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 t gcesareni Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm. SIGNOR-178483 0.2 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 0.8 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192623 0.8 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 0.7 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 0.453 ADCY1 protein Q08828 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-265003 0.8 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 0.2 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 0.349 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 0.2 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 0.672 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12050114 t gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. SIGNOR-88716 0.354 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 0.8 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser246 FPKSRLSsVSVTYCS 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-183596 0.2 TRAF6 protein Q9Y4K3 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 f miannu TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. SIGNOR-253046 0.7 HSPG2 protein P98160 UNIPROT PTPRS protein Q13332 UNIPROT up-regulates binding 9606 11865065 t gcesareni We demonstrate here that cptpsigma is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (hspgs) agrin and collagen xviii. SIGNOR-115246 0.253 RPS6KA1 protein Q15418 UNIPROT CDC34 protein P49427 UNIPROT down-regulates quantity by destabilization phosphorylation Thr162 KGKDREYtDIIRKQV -1 27786305 t miannu RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation. SIGNOR-277330 0.335 CSNK2A1 protein P68400 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Thr1318 YQNTTAMtIYENLAP 9606 BTO:0002181 24583284 t miannu CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation. SIGNOR-277876 0.2 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 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-203302 0.2 ANK1 protein P16157 UNIPROT ATP2A1 protein O14983 UNIPROT down-regulates activity binding 9986 28487373 t lperfetto We recently reported that small ankyrin 1 (sAnk1) interacts with the sarco(endo)plasmic reticulum Ca2+-ATPase in skeletal muscle (SERCA1) to inhibit its activity. SIGNOR-265927 0.293 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265440 0.2 CYP1B1 protein Q16678 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000093 8790407 t Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. SIGNOR-269756 0.8 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16446360 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-143988 0.962 acadesine chemical CHEBI:28498 ChEBI PRKAG1 protein P54619 UNIPROT up-regulates chemical activation 9606 SIGNOR-C15 16879084 t gcesareni The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c. SIGNOR-148337 0.8 hsa-mir-223 mirna URS000037EC34_9606 RNAcentral Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 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-255763 0.4 NFIX protein Q14938 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR form complex binding 10090 BTO:0000165 20178747 t llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. SIGNOR-238016 0.2 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194628 0.8 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr84 EHSDSEMyVMPAEEN 9606 BTO:0000776 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96048 0.806 IQSEC2 protein Q5JU85 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 27009485 f miannu These data demonstrate that the reduction of BRAG1 results in a reduction of synaptic transmission. Together with the data showing that overexpression of BRAG1 enhances synaptic transmission, these data highlight the role of BRAG1 in the bidirectional regulation of synaptic transmission. SIGNOR-264905 0.7 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 0.2 MMP1 protein P03956 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly774 RGDVGEKgPEGAPGK -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272338 0.445 SREBF1 protein P36956 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 10090 15589694 f lperfetto In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis), SIGNOR-228614 0.7 RIMS3 protein Q9UJD0 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-264384 0.266 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 0.384 CSMD1 protein Q96PZ7 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 22538441 f miannu CSMD1 inhibits tumor growth, angiogenesis, and survival rate in vivo SIGNOR-265150 0.7 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 0.375 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 16051226 t gcesareni Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44). SIGNOR-139102 0.76 CRBN protein Q96SW2 UNIPROT IKZF3 protein Q9UKT9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000725 29496670 t miannu IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase. SIGNOR-272319 0.581 tyrphostin AG 1478 chemical CHEBI:75404 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189377 0.8 EGFR protein P00533 UNIPROT KCNN1 protein Q92952 UNIPROT up-regulates activity phosphorylation Tyr109 KRKRLSDyALIFGMF 9606 BTO:0000007 23496660 t miannu These results demonstrate the novel information that hSKCa1 channels are inhibited by genistein, T25 and AG556 via EGFR tyrosine kinase inhibition, which is related to the phosphorylation of Tyr(109) in the N-terminus.  SIGNOR-276490 0.2 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR JARID2 protein Q92833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435416 t lperfetto JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells| we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein.| Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS SIGNOR-249597 0.2 SLC25A1 protein P53007 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity relocalization 9606 29651165 t SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate SIGNOR-267289 0.8 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 0.942 NFE2 protein Q16621 UNIPROT HBD protein P02042 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-251843 0.393 MAPK14 protein Q16539 UNIPROT CASP3 protein P42574 UNIPROT down-regulates phosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 14970175 t gcesareni Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response. SIGNOR-122099 0.775 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 0.459 PCSK2 protein P16519 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-268725 0.2 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 0.941 CXCR4 protein P61073 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0005387 19584257 f lperfetto However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype SIGNOR-252266 0.7 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Thr447 NASGSTStPAPSRTA 10653665 t Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic. SIGNOR-251219 0.364 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser750 QTEEEEHsCLEQAS 9606 18957422 t lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma SIGNOR-181806 0.343 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 0.8 HDAC2 protein Q92769 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264499 0.703 NXF1 protein Q9UBU9 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR form complex binding 9606 17001072 t miannu Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression. SIGNOR-149880 0.489 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Ser372 VAATPPPsTASAPAA 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-146220 0.519 EEF1A1P5 protein Q5VTE0 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 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-269546 0.8 APH1A protein Q96BI3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12522139 t gcesareni Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity. SIGNOR-97068 0.947 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 0.497 SB 505124 chemical CHEBI:100922 ChEBI ACVR1C protein Q8NER5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206739 0.8 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 0.2 SWI/SNF complex complex SIGNOR-C92 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity binding 9606 20506188 t miannu Our findings indicate that RUNX1 interacts with the human SWI/SNF complex to control hematopoietic-specific gene expression. SIGNOR-261965 0.456 HBB protein P68871 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT down-regulates activity 9606 15367436 f Regulation of binding miannu Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher. SIGNOR-251748 0.2 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 0.265 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t gcesareni Mutation of Rad51 Tyr315, but not Tyr205, Tyr191, or Tyr54 to phenylalanine abolished Rad51 tyrosine phosphorylation by c-Abl (Fig. 3 b). These results strongly suggest that c-Abl phosphorylates Rad51 Tyr315 in vivo SIGNOR-247594 0.773 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 0.833 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser25 AERGLGPsPAGDGPS 10090 BTO:0002572 23332762 t lperfetto Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. SIGNOR-209776 0.263 NR4A3 protein Q92570 UNIPROT BBC3 protein Q9BXH1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 t miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. SIGNOR-259396 0.2 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252327 0.65 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001412 8394219 f We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. SIGNOR-255723 0.7 UBE2D2 protein P62837 UNIPROT TRIM5 protein Q9C035 UNIPROT up-regulates activity binding 9606 BTO:0000567 18312418 t miannu Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B.  SIGNOR-271670 0.457 TOP2B protein Q02880 UNIPROT SST protein P61278 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-242305 0.2 ZC3H12A protein Q5D1E8 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity post transcriptional regulation 9606 BTO:0000007 30842549 t Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA SIGNOR-259943 0.2 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 0.8 IL21 protein Q9HBE4 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-108858 0.61 U2AF2 protein P26368 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR form complex binding 9606 8647433 t miannu The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35). SIGNOR-41948 0.2 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207212 0.8 WNT2 protein P09544 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-131730 0.673 HOMER1 protein Q86YM7 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity binding 9606 BTO:0000938 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264243 0.744 THEM4 protein Q5T1C6 UNIPROT AKT1 protein P31749 UNIPROT down-regulates binding 9606 11598301 t gcesareni Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308. SIGNOR-111003 0.699 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 0.94 RXRA protein P19793 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). SIGNOR-270292 0.723 EHF protein Q9NZC4 UNIPROT DCDC2 protein Q9UHG0 UNIPROT down-regulates quantity by repression transcriptional regulation 22733135 f Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter. SIGNOR-254279 0.264 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 0.8 PRKCA protein P17252 UNIPROT L1CAM protein P32004 UNIPROT down-regulates activity phosphorylation Thr1172 ARPMKDEtFGEYRSL 9606 BTO:0000304 20335502 t miannu CKII phosphorylates T1172 of the L1 CD and phosphorylation of T1172 is responsible for loss of 2C2 signal. SIGNOR-276283 0.2 BCL3 protein P20749 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 15469820 t gcesareni We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6 SIGNOR-129801 0.427 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 9606 12040173 t lperfetto The binding of tnf to tnf-r1 triggers a series of intracellular events that ultimately result in the activation of two major transcription factors, nuclear factor kb (nf-kb) and c-jun. SIGNOR-88216 0.93 MAP1LC3C protein Q9BXW4 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates activity 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-266795 0.594 IL26 protein Q9NPH9 UNIPROT IL20RA protein Q9UHF4 UNIPROT up-regulates binding 9606 BTO:0001253 17208301 t gcesareni The mrna expression level of il10, il19, il20, il22, il24, il26, il28b, il29 and their receptors il10ra, il10rb, il20ra, il20rb, il22ra1, il22ra2, il28ra was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time pcr (qrt-pcr). SIGNOR-151920 0.601 CDH5 protein P33151 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265867 0.76 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 0.326 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser57 KKDRFYRsILPGDKT 9534 BTO:0000298 9032240 t miannu Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation. SIGNOR-250219 0.2 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 0.7 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating K-Ras-RASSF1A€“MST2 complex, as reported here. SIGNOR-249588 0.697 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT unknown dephosphorylation 9606 BTO:0000527 15808505 t gcesareni These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3 SIGNOR-135008 0.621 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 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-267857 0.7 CILK1 protein Q9UPZ9 UNIPROT CILK1 protein Q9UPZ9 UNIPROT up-regulates phosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 15988018 t lperfetto Ick is activated by dual phosphorylation of the tdy motif. Phosphorylation of tyr-159 in the tdy motif requires ick autokinase activity SIGNOR-138424 0.2 MAPK3 protein P27361 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 t 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-32757 0.299 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2276 SFKSALSerPSKSPA -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259120 0.474 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 0.697 SOX4 protein Q06945 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000848 22689055 t .... showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least twofold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown SIGNOR-258987 0.395 PKA proteinfamily SIGNOR-PF17 SIGNOR BRSK2 protein Q8IWQ3 UNIPROT up-regulates activity phosphorylation Thr260 VDAARRLtLEHIQKH -1 16870137 t miannu BRSK2 is activated by cyclic AMP-dependent protein kinase A through phosphorylation at Thr260 SIGNOR-276056 0.2 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 0.249 IL2RB protein P14784 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain SIGNOR-204972 0.631 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t lperfetto Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro. SIGNOR-121869 0.579 MAP2K2 protein P36507 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000142 1411546 t inferred from 70% of family members gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-269895 0.2 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Thr2068 LLDEYNVtPSPPGTV 9606 BTO:0000007 12794074 t lperfetto We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093. SIGNOR-101570 0.481 imiquimod chemical CHEBI:36704 ChEBI TLR8 protein Q9NR97 UNIPROT up-regulates activity chemical activation 9606 15661881 t miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. SIGNOR-259245 0.8 Fostamatinib disodium chemical CID:25008120 PUBCHEM SYK protein P43405 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206373 0.8 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 0.799 PP121 chemical CHEBI:50915 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206289 0.8 CBL protein P22681 UNIPROT INSR protein P06213 UNIPROT down-regulates ubiquitination 9606 11498022 t gcesareni Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor SIGNOR-109688 0.528 FOXL2 protein P58012 UNIPROT CYP11A1 protein P05108 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254177 0.39 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 0.262 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 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-249465 0.637 SETD1B protein Q9UPS6 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546568 t miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. SIGNOR-265578 0.2 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 0.456 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 0.2 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 0.8 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 0.326 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 0.2 7-Hydroxystaurosporine chemical CID:72271 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni The clinical use of ucn-01, the first chk1 inhibitor evaluated in humans, is limited by its prolonged plasma half-life due to extensive plasma binding to alfa1 acidic glycoprotein SIGNOR-163222 0.8 CLK4 protein Q9HAZ1 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates activity phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 BTO:0000007 35592512 t done miannu Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor. SIGNOR-274117 0.2 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 0.912 RHOA protein P61586 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-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-192114 0.7 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 0.8 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 0.2 RIN1 protein Q13671 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12783862 t gcesareni The interaction between egfr and rin1 delineates a novel signal transduction pathway between egfr and its effectors, rin1, rab5a, and ras, which together coordinate and regulate both signaling and membrane trafficking. SIGNOR-101530 0.403 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 0.2 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 0.735 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR KRAS protein P01116 UNIPROT up-regulates 9606 19483050 f lperfetto A recurrent gene fusion between echinoderm microtubule-associated protein-like 4 (EML4;and, occasionally, of other fusion partners) and the anaplastic lymphoma kinase (ALK) geneoccurs in of NSCLCs , resulting in activation of a potent ALK fusion protein.ALK fusion protein is usually found in never-smoker subjects. Although relatively rare, therelative paucity of fusion proteins known to contribute to lung cancer pathogenesis makes this a finding of biological interest. Although present understanding of the ALK fusion protein is limited, it may play a role in activating RAS. Thus it is negatively associated with thepresence of KRAS or EGFR mutations, and may favour ADC histology and never-smokerstatus. SIGNOR-253216 0.2 Cyclopamine chemical CHEBI:4021 ChEBI CXCL1 protein P09341 UNIPROT down-regulates chemical inhibition 9606 16885213 t gcesareni Cyclopamine and other inhibitors of hh signaling were found to inhibit smo coupling to gi in a manner consistent with inverse agonism. SIGNOR-148469 0.8 ROCK1 protein Q13464 UNIPROT LPP protein Q93052 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 22886954 f miannu Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression SIGNOR-198118 0.2 RPS6KA1 protein Q15418 UNIPROT 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-182497 0.543 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 0.2 LRRK2 protein Q5S007 UNIPROT LARS1 protein Q9P2J5 UNIPROT down-regulates activity phosphorylation Thr293 NIFLVAAtLRPETMF -1 30411383 t miannu In this study, we elucidated that leucyl-tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2-meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers. SIGNOR-277417 0.2 APBA1 protein Q02410 UNIPROT Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 11036064 f miannu As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses SIGNOR-264043 0.7 E2F1 protein Q01094 UNIPROT ELF4 protein Q99607 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20805247 f miannu we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. SIGNOR-253849 0.246 AKT1 protein P31749 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 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b 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-245416 0.792 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR3 protein Q9UBY5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193564 0.8 ABL1 protein P00519 UNIPROT SPTLC1 protein O15269 UNIPROT down-regulates phosphorylation Tyr164 KTEEAIIySYGFATI 9606 23629659 t llicata We demonstrated that the er-resident human protein serine palmitoyltransferase long chain-1 (sptlc1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at tyr(164) by the tyrosine kinase abl. this occurred through the specific abl-mediated phosphorylation of sptlc1 on tyr164, leading to the attenuation of its activity. SIGNOR-202003 0.2 ADGRG1 protein Q9Y653 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0000142 31515243 t lperfetto Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis SIGNOR-272344 0.2 PKCtheta/Nfix complex SIGNOR-C121 SIGNOR MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 20178747 t llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. SIGNOR-238022 0.337 TAF2 protein Q6P1X5 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-263931 0.885 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 0.649 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 0.858 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 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-268104 0.8 HMOX1 protein P09601 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-251813 0.253 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding -1 8440710 t 2 miannu CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer. SIGNOR-240397 0.51 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates activity sumoylation Lys298 MGVVECAkHELLQPF 9606 BTO:0000007 19946338 t gcesareni Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity. SIGNOR-249657 0.336 KAT2A protein Q92830 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269599 0.2 CDK1 protein P06493 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity by destabilization phosphorylation Ser277 ASPGSLHsPQQLAEE 10090 BTO:0001077 11466319 t miannu  The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.  SIGNOR-275979 0.296 MAPK1 protein P28482 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-120455 0.259 EIF5 protein P55010 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-269163 0.752 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 0.8 SMURF2 protein Q9HAU4 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps. SIGNOR-193119 0.503 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation -1 11287604 t inferred from 70% family members lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 SIGNOR-270200 0.2 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 0.383 AP2S1 protein P53680 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 t lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit SIGNOR-260421 0.916 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 0.382 KRN-633 chemical CID:9549295 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193585 0.8 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni In mammals, pdhc is tightly regulated by phosphorylation-dephosphorylation of three serine residues in the thiamin-dependent pyruvate dehydrogenase (e1) component. In vivo, inactivation of human pdhc correlates mostly with phosphorylation of serine 264, which is located at the entrance of the substrate channel leading to the active site of e1. SIGNOR-154656 0.686 leukotriene B4(1-) smallmolecule CHEBI:57461 ChEBI LTB4R protein Q15722 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-257534 0.8 NLGN3 protein Q9NZ94 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-264167 0.825 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser870 KEDSAYGsQSVEQEA 10090 BTO:0000785 15084608 t lperfetto Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52. SIGNOR-124230 0.791 Pravadoline chemical CID:56463 PUBCHEM PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206322 0.8 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 0.2 SMAD7 protein O15105 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates 9606 17438144 f gcesareni Smad7 repressed smad3/4-, smad2/4-, and smad1/4-enhanced reporter gene expression. SIGNOR-154390 0.581 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 0.686 471905-41-6 chemical CID:9803433 PUBCHEM APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194358 0.8 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 0.304 RAC3 protein P60763 UNIPROT CIB1 protein Q99828 UNIPROT up-regulates activity binding 10029 BTO:0000246 11756406 t Gianni We here report that CIB, a protein that binds to the alpha(IIb)beta(3) fibrinogen receptor, interacts exclusively with activated (V12) Rac3 but not Rac1 or Rac2. Binding of V12Rac3 to CIB was mediated by the C-terminal end of Rac3 and by Rac3 membrane localization SIGNOR-269060 0.348 RAC1 protein P63000 UNIPROT ALS2 protein Q96Q42 UNIPROT up-regulates activity binding 9606 BTO:0000567 30485418 t miannu Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane ruffles, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion. SIGNOR-277777 0.532 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259860 0.334 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169514 0.518 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 0.444 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 0.8 IGF2 protein P01344 UNIPROT INSR protein P06213 UNIPROT up-regulates binding 9606 9281335 t fspada Therefore, these results provide genetic evidence that the growth-promoting function of igf-ii during mouse embryogenesis is mediated in part by signaling through the insulin receptor. SIGNOR-50719 0.707 CEP250 protein Q9BV73 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24769208 f lperfetto C-NAP1 which is located in the proximal ends of the centriole is an important factor for maintaining cohesion of centrioles in interphase SIGNOR-265498 0.7 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 0.8 HIPK3 protein Q9H422 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD -1 11034606 t FIST/HIPK3 causes FADD phosphorylation, thereby promoting FIST/HIPK3-FADD-Fas interaction.¬† Phosphorylation occurs on Ser194 close to the COOH terminus of human FADD| Fas ligand-induced activation of Jun NH(2)-terminal kinase is impaired by overexpressed active FIST/HIPK3 SIGNOR-251272 0.436 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12038972 t gcesareni Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i) SIGNOR-88143 0.451 ATP smallmolecule CHEBI:15422 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-268079 0.8 LPAR6 protein P43657 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-257120 0.2 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 9865696 t lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. SIGNOR-232126 0.861 CHEK2 protein O96017 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr284 APTRTPAtAPVPARA 9606 18971944 t llicata Chk2 formed a complex with xrcc1, the ber scaffold protein, and phosphorylated xrcc1 in vivo and in vitro at thr(284). our results are consistent with the phosphorylation of xrcc1 by atm-chk2 facilitating recruitment of downstream ber proteins to the initial damage recognition/excision step to promote ber. SIGNOR-181816 0.515 TNF protein P01375 UNIPROT LZTR1 protein Q8N653 UNIPROT down-regulates quantity by destabilization 9606 16356934 f Induction of Apoptosis by Staurosporine, TNFŒ±, and TRAIL Induces Degradation of LZTR-1 by Caspase- and Proteasome-dependent Pathways SIGNOR-253612 0.2 DOK1 protein Q99704 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-257691 0.294 EZR protein P15311 UNIPROT FES protein P07332 UNIPROT up-regulates relocalization 9606 18046454 t miannu The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin. SIGNOR-159496 0.395 SMAD3 protein P84022 UNIPROT NOTCH1 protein P46531 UNIPROT 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-119374 0.543 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 0.394 ATG13 protein O75143 UNIPROT ULK2 protein Q8IYT8 UNIPROT up-regulates binding 9606 19225151 t gcesareni He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk SIGNOR-184123 0.75 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 0.293 prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 3308494 f apalma The results suggest a role for prostanoids in the regulation of both human myoblast proliferation and differentiation SIGNOR-255362 0.7 NF1 protein P21359 UNIPROT ADCY8 protein P40145 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-204289 0.398 glycine smallmolecule CHEBI:15428 ChEBI GLRA3 protein O75311 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-264982 0.8 p38 proteinfamily SIGNOR-PF16 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation -1 12171600 t inferred from 70% family members miannu Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%. SIGNOR-270127 0.2 PIM proteinfamily SIGNOR-PF34 SIGNOR RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 t llicata In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276. SIGNOR-259411 0.2 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 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-70457 0.747 AKT proteinfamily SIGNOR-PF24 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata Akt regulates ranbp3 phosphorylation in vitro and in vivo SIGNOR-160900 0.2 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 0.416 PPP2CB protein P62714 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 t K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts. SIGNOR-248588 0.2 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;VIRAL ABL gcesareni SIGNOR-193372 0.8 ETV3 protein P41162 UNIPROT ETV3 protein P41162 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22028471 t miannu ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation. SIGNOR-262778 0.2 N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide chemical CHEBI:94175 ChEBI SHH protein Q15465 UNIPROT down-regulates chemical inhibition 9606 BTO:0001253 19151731 t gcesareni More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch. SIGNOR-183465 0.8 PPP3CA protein Q08209 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-248692 0.629 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 SIGNOR-252798 0.2 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 0.2 U0126 chemical CHEBI:90693 ChEBI MAP2K2 protein P36507 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-62895 0.8 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Thr161 LGLPEEEtELDNLTE -1 9407077 t llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. SIGNOR-251024 0.473 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation Tyr1035 IETDKEYyTVKDDRD -1 12559972 t Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD) SIGNOR-251364 0.536 SLC18A2 protein Q05940 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). |VMAT2 also appears to mediate histamine transport into dense granules SIGNOR-265997 0.2 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser293 EESYDTEsEFTEFTE 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-40510 0.581 FKBP4 protein Q02790 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 10090 BTO:0000947 19545546 t We noted that FK506 altered nuclear localization of the GR and inhibited expression of GR-responsive genes. Furthermore, si-RNA knockdown of FKBP4 gene, coding for the immunophilin FKBP52, inhibited cortisol-activated GR nuclear translocation SIGNOR-252034 0.72 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 0.2 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser676 LSQRFTFsPGQDIQL 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-84996 0.441 AKT1 protein P31749 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser134 ANLNRSTsVPENPKS 9606 BTO:0000731 24291004 t lperfetto Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus SIGNOR-252543 0.486 PRKACA protein P17612 UNIPROT GP1BB protein P13224 UNIPROT down-regulates activity phosphorylation Ser191 ARAAARLsLTDPLVA -1 2504723 t miannu Platelet glycoprotein Ib beta is phosphorylated on serine 166 by cyclic AMP-dependent protein kinase. phosphorylation of this residue may contribute to the inhibitory actions of cyclic AMP by inhibiting collagen-induced polymerization of actin. SIGNOR-249986 0.312 TSC22D3 protein Q99576 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates activity binding 9606 BTO:0000007 11468175 t GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. SIGNOR-253298 0.327 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 0.361 (-)-anisomycin chemical CHEBI:338412 ChEBI JUN protein P05412 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189632 0.8 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 0.2 SP1 protein P08047 UNIPROT MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 t lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. SIGNOR-241490 0.319 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR UBTF protein P17480 UNIPROT down-regulates phosphorylation 9606 11741541 t inferred from 70% family members lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-270181 0.2 PRKACA protein P17612 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 10090 BTO:0000944 23644383 t inferred from 70% of family members milica Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381. SIGNOR-269863 0.2 MECP2 protein P51608 UNIPROT GRIA2 protein P42262 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 22262897 t Luana Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. SIGNOR-264684 0.323 TNF protein P01375 UNIPROT DNAH10 protein Q8IVF4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 31836722 f miannu The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation. SIGNOR-265551 0.2 TP53 protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 10329733 f lperfetto P53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. SIGNOR-271677 0.749 SLC20A1 protein Q8WUM9 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 11009570 t lperfetto Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 SIGNOR-270579 0.8 ANGPT2 protein O15123 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 9723709 t lperfetto Angiopoietin-1 and -2, bound to tek with similar affinities, and angiopoietin-1 effectively induced tek phosphorylation in hematopoietic cells. Angiopoietin-2 also induced a low level of tek phosphorylation and weakened the phosphorylation induced by angiopoietin-1 SIGNOR-59808 0.924 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 0.8 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207857 0.8 APEX1 protein P27695 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14630715 t Luana These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8.  SIGNOR-261564 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 12676795 f Luana Activation of the Ras-MAPK/Erk signaling cascade is essential for neurotrophin-promoted differentiation of neurons and PC12 cells. SIGNOR-264978 0.7 ARRY-520 chemical CID:44224257 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189891 0.8 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 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-261368 0.265 PRKACA protein P17612 UNIPROT CD44 protein P16070 UNIPROT up-regulates phosphorylation Ser697 AVEDRKPsGLNGEAS 9606 16785995 t lperfetto Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains. SIGNOR-147208 0.2 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 0.843 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 0.709 TRIM32 protein Q13049 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19269368 t miannu TRIM32 ubiquitinates and degrades the transcription factor c-Myc but also binds Argonaute-1 and thereby increases the activity of specific microRNAs. SIGNOR-278676 0.456 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT down-regulates activity phosphorylation Ser38 ASEHRKSsKPIMEKR -1 9389649 t lperfetto Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. SIGNOR-248993 0.329 PITX2 protein Q99697 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 20978076 f gcesareni We show that pitx2 is crucial for the onset of myod gene expression in limb muscle progenitors and that it acts on the myod core enhancer. SIGNOR-169107 0.436 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 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252802 0.2 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 0.8 Opsonization phenotype SIGNOR-PH150 SIGNOR Membrane attack complex complex SIGNOR-C313 SIGNOR up-regulates -1 30552328 f lperfetto CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers SIGNOR-263455 0.7 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 0.364 GSK3A protein P49840 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Ser1387 QPLSKSSsSPELQTL 16959574 t gcesareni Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. SIGNOR-149377 0.362 KHSRP protein Q92945 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10090 BTO:0000165 16364914 t lperfetto Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK]) SIGNOR-235859 0.252 CBLB protein Q13191 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000661 8626404 t lperfetto Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2. SIGNOR-236051 0.567 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 0.607 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194548 0.8 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates quantity by destabilization sumoylation Lys866 PLNLTFIkKEFSNSN 9534 BTO:0001538 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-269113 0.331 DUSP10 protein Q9Y6W6 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 10391943 t gcesareni Mkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk, but not mapk/erk. p38 is a preferred substrate SIGNOR-68983 0.695 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK14 protein Q16539 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni SIGNOR-189699 0.8 UIMC1 protein Q96RL1 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 17525342 t gcesareni Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control SIGNOR-155201 0.91 Fatty acid stimulus SIGNOR-ST19 SIGNOR SIRT6 protein Q8N6T7 UNIPROT up-regulates 9606 25815987 t miannu Intriguingly, SIRT6 is chromatin bound, controls lipid metabolism, and is enzymatically activated by fatty acids SIGNOR-268156 0.7 WNT10B protein O00744 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 12055200 f fspada We have identified wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro SIGNOR-89131 0.7 tyrphostin B42 chemical CHEBI:131968 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189386 0.8 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216457 0.491 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCE protein Q02156 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-242590 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation 9606 22085529 t miannu Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells. SIGNOR-259029 0.2 PRKG1 protein Q13976 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates phosphorylation Thr276 SIWKGVKtSGKVVWV 9606 BTO:0000567 17913921 t gcesareni These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5. SIGNOR-158186 0.382 USP8 protein P40818 UNIPROT RNF41 protein Q9H4P4 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 23750007 t irozzo Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins. SIGNOR-259105 0.88 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159458 0.257 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 0.705 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser392 VSGASPEsISSLLSE -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-262909 0.701 PDGFRB protein P09619 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 t gcesareni The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency. SIGNOR-64740 0.615 RIN1 protein Q13671 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 11784866 t gcesareni We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1. SIGNOR-113967 0.636 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 0.34 tofacitinib citrate chemical CHEBI:71197 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207311 0.8 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. SIGNOR-135384 0.792 GFI1 protein Q99684 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 20861919 f irozzo In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. SIGNOR-256084 0.7 NUMA1 protein Q14980 UNIPROT TUBG1 protein P23258 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-117203 0.618 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 0.63 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 0.421 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser103 ESSLSSEsSESSDAG 9606 BTO:0000567 21807946 t miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). SIGNOR-276349 0.2 DVL1 protein O14640 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 17569865 t amattioni The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization. SIGNOR-156072 0.707 TTK protein P33981 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Ser928 SRLATNTsAPDLKNV 9606 BTO:0000567 31253867 t miannu We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.  SIGNOR-277458 0.2 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 0.706 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275875 0.2 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 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 0.2 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 0.8 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 0.8 ABL1 protein P00519 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr222 IGAGKGKyYAVNFPM 10116 25219501 t Manara C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease. SIGNOR-260928 0.285 GRIK5 protein Q16478 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268276 0.8 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000038; BTO:0000675 28408316 f irozzo Forced expression of LRP1B in SW480 and SW620 cells inhibited the growth, migration and anchorage-independent growth of cancer cells. SIGNOR-259091 0.7 VPS72 protein Q15906 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-269290 0.67 THR proteinfamily SIGNOR-PF84 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 t scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. SIGNOR-267275 0.2 RRM2 protein P31350 UNIPROT Ribonucleotide reductase complex SIGNOR-C233 SIGNOR form complex binding 9606 14583450 t miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. SIGNOR-259364 0.933 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 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-235587 0.661 GSK3B protein P49841 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser58 SFFKEPDsGSHSRQS 9606 BTO:0002181 22692215 t miannu GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3  phosphorylation, whereas the Ser-66 is not (Fig. 4D). SIGNOR-277646 0.2 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 0.599 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 0.601 GRPR protein P30550 UNIPROT PLA2G1B protein P04054 UNIPROT up-regulates binding 9606 17251915 t gcesareni Grpr stimulation activates phospholipase a2 (pla2) and cyclooxygenase 2 (cox2), which leads to prostaglandin e2 (pge2) production and ep receptor stimulation. SIGNOR-152756 0.255 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 0.334 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 0.8 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Ser165 HNHTTHMsLVGTFPW 9606 15342622 t gcesareni Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation. SIGNOR-128573 0.2 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival. SIGNOR-157790 0.84 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 9889196 t lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. SIGNOR-63895 0.942 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR AR protein P10275 UNIPROT down-regulates activity dephosphorylation Ser83 QQQQQETsPRQQQQQ 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-254759 0.297 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation 9606 9792677 t gcesareni Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1 SIGNOR-60995 0.604 TUBB1 protein Q9H4B7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10116 17118269 f lperfetto However, evidence suggests that the detyrosination/tyrosination cycle of alpha-tubulin may be linked in some cell types to cell division and proliferationNF-Y SIGNOR-242138 0.7 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Ser249 LSPIDMEsQERIKAE -1 1846781 t lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. SIGNOR-18684 0.712 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2A protein P29274 UNIPROT up-regulates activity binding -1 14662005 t Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. SIGNOR-268420 0.8 PRKAG2 protein Q9UGJ0 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates activity phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 t miannu STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE SIGNOR-277297 0.2 CXCR4 protein P61073 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0000007 33073183 t Marta Tosoni Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner SIGNOR-278102 0.561 EDN1 protein P05305 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12847114 f Regulation of expression miannu βMHC expression was markedly augmented by PE and ET, suggesting the transformation of myosin. endothelin-1 (ET) SIGNOR-251955 0.28 AFF2 protein P51816 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity binding 9606 17135274 t miannu Af4 associates with P-TEFb and stimulates its kinase activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity SIGNOR-266801 0.389 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 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-251858 0.464 NFATC1 protein O95644 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-270537 0.7 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 0.8 OSU-03012 chemical CHEBI:131196 ChEBI PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-197715 0.8 RPLP1 protein P05386 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-262450 0.828 DPM2 protein O94777 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 t lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. SIGNOR-262564 0.786 PEX26 protein Q7Z412 UNIPROT PEX6 protein Q13608 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-253614 0.78 nintedanib chemical CHEBI:85164 ChEBI FGFR2 protein P21802 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-257806 0.8 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 t lperfetto Vav interacts with the tyrosine kinase syk SIGNOR-107049 0.92 NDUFA6 protein P56556 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262157 0.836 FBXO5 protein Q9UKT4 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates ubiquitination 9606 11751633 t gcesareni Emi1 binds cdh1 and inhibits apc-cdh1 activity. SIGNOR-113385 0.756 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. SIGNOR-244930 0.8 WNT5B protein Q9H1J7 UNIPROT FZD6 protein O60353 UNIPROT up-regulates binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141443 0.668 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 24702154 t Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils SIGNOR-254356 0.936 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 28117675 t miannu FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs) SIGNOR-272787 0.427 AKT2 protein P31751 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser167 GGRERLAsTNDKGSM 9534 BTO:0001538 11139588 t AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. SIGNOR-251490 0.509 CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 37104883 f lperfetto Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. SIGNOR-273191 0.7 2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide chemical CHEBI:91426 ChEBI SYK protein P43405 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 30744170 t lperfetto The Selective SYK Inhibitor BAY 61-3606 Enhances the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells SIGNOR-262020 0.8 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates ubiquitination 9606 19759537 t gcesareni Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-188036 0.697 CSNK2A1 protein P68400 UNIPROT C1R protein P00736 UNIPROT down-regulates activity phosphorylation Ser206 TEASGYIsSLEYPRS -1 8635594 t llicata We provide evidence that this kinase phosphorylates Clr at the level of Ser189. | Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex. SIGNOR-250833 0.307 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 0.7 ICE1 protein Q9Y2F5 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-193486 0.571 CTSK protein P43235 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 11920402 f lperfetto Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. SIGNOR-253318 0.7 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 0.283 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 0.679 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 0.352 AKT1 protein P31749 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-252472 0.775 WNT7A protein O00755 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates activity binding 9606 BTO:0000972 31886205 t Marta Tosoni These findings suggested that Wnt7a upregulated P21 and P27 by inactivating SKP2. SIGNOR-278876 0.2 BAF250b E3 ligase complex SIGNOR-C522 SIGNOR Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271441 0.2 PTPRG protein P23470 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity dephosphorylation Tyr783 DTGENPIyKSAVTTV -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254706 0.265 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT up-regulates ubiquitination 9606 BTO:0000938 BTO:0000142 16862145 t gcesareni Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15 SIGNOR-148218 0.2 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270891 0.473 CSNK2A2 protein P19784 UNIPROT KIF1C protein O43896 UNIPROT unknown phosphorylation Ser1092 PRMRRQRsAPDLKES -1 10559254 t llicata Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family. SIGNOR-251010 0.31 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 0.8 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 0.597 3-phenanthryl hydrogen sulfate chemical CHEBI:37459 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. SIGNOR-258438 0.8 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 0.371 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR NRAS protein P01111 UNIPROT up-regulates activity 9534 8402896 f miannu BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. SIGNOR-261506 0.2 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 0.7 EIF4B protein P23588 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 t Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability SIGNOR-261293 0.867 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 20708156 t gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination SIGNOR-167513 0.345 TRIM32 protein Q13049 UNIPROT PBRM1 protein Q86U86 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26057645 t miannu TRIM32 ubiquitination of PB1 leads to its protein degradation. SIGNOR-278735 0.2 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 BTO:0001412 12769847 t llicata We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.  SIGNOR-251049 0.347 KAT2A protein Q92830 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity acetylation 24870244 t lperfetto The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. SIGNOR-275498 0.2 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 0.7 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe635 HHQKLVFfAEDVGSN 9606 10931940 t lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Aβ is produced from the Aβ precursor protein (APP) by two proteolytic events. A β-secretase activity cleaves APP at the N terminus of Aβ (β site) between amino acids Met-671 and Asp-672 |We show here that BACE2 cleaves APP at its β site and more efficiently at sites within the Aβ region of APP, after Phe-19 and Phe-20 of Aβ. SIGNOR-261775 0.544 POGLUT1 protein Q8NBL1 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22872643 t gcesareni O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. O-glucose can be elongated by xylose to the trisaccharide, xylalfa1-3xylalfa1-3glcbeta1-o-ser, whose synthesis is catalyzed by the consecutive action of three glycosyltransferases. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus. SIGNOR-198716 0.575 NEDD4 protein P46934 UNIPROT SYK protein P43405 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 11046148 t miannu The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases.  SIGNOR-272581 0.291 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr344 PPEQETFyEQPPLVQ 9606 BTO:0000782 14557276 t lperfetto We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. SIGNOR-118695 0.64 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 0.426 PTPMT1 protein Q8WUK0 UNIPROT phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI up-regulates chemical modification 10090 21641550 t lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. SIGNOR-267025 0.8 FYN protein P06241 UNIPROT ARHGAP33 protein O14559 UNIPROT down-regulates phosphorylation Tyr406 PLLTYQLyGKFSEAM 9606 16777849 t acerquone Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap SIGNOR-147156 0.461 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 0.413 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 0.465 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 0.762 SHC1 protein P29353 UNIPROT MAPK1 protein P28482 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-242622 0.713 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.792 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 12809556 t gcesareni Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation SIGNOR-102294 0.448 ATM protein Q13315 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity phosphorylation Ser219 SKLLMIIsQKDTFHS 9606 BTO:0000567 11375976 t lperfetto Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo. SIGNOR-108419 0.571 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation 9606 10567572 t amattioni Jnk was capable of phosphorylating bcl-2. Phosphorylation of bcl-2 inactivates the molecule SIGNOR-72364 0.582 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser173 VKKNPHHsQWGDMKL -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-250579 0.611 SLC24A1 protein O60721 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264395 0.8 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130;BTO:0000150;BTO:0000551 BTO:0000975 9129046 t gcesareni The major ligand for p-selectin on leukocytes is p-selectin glycoprotein ligand-1 (PSGL-1) SIGNOR-47625 0.927 CBLB protein Q13191 UNIPROT SYK protein P43405 UNIPROT down-regulates quantity ubiquitination 9606 12771181 t miannu In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling. SIGNOR-278754 0.696 RPS6KB2 protein Q9UBS0 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway SIGNOR-178594 0.2 CCNC protein P24863 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-266685 0.922 TRIO protein O75962 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260579 0.692 MTA1 protein Q13330 UNIPROT MTA3 protein Q9BTC8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 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-254595 0.655 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 0.2 JUN protein P05412 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-59867 0.75 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75017 0.791 CALM2 protein P0DP24 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t miannu The calmodulin-binding region is located between amino acids 51 and 96 SIGNOR-266321 0.461 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 0.32 CSF2 protein P04141 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001571 2479426 f Regulation of expression miannu Granulocyte-macrophage colony-stimulating factor reactivates fetal hemoglobin synthesis in erythroblast clones from normal adults. SIGNOR-251776 0.2 KPNA2 protein P52292 UNIPROT RNMT protein O43148 UNIPROT down-regulates activity binding 9606 26942677 t lperfetto KPNA2 Inhibits RNMT Activity|We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. SIGNOR-265502 0.412 Calcineurin complex SIGNOR-C155 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252322 0.558 MLH1 protein P40692 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR form complex binding 9606 10542278 t miannu We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_. SIGNOR-71768 0.694 KATNAL2 protein Q8IYT4 UNIPROT TUBE1 protein Q9UJT0 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001363 29136647 t miannu KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin SIGNOR-267176 0.2 HSP90AA1 protein P07900 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21511880 t gcesareni We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region. SIGNOR-251667 0.735 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 0.7 ANK3 protein Q12955 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity binding 9606 BTO:0000007 17620337 t miannu Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. SIGNOR-266710 0.323 RPS6KA5 protein O75582 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 t gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-265348 0.2 TNFRSF13C protein Q96RJ3 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 BTO:0000776 24432023 f lperfetto Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures. SIGNOR-204361 0.7 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser400 SRDESTDsGLSMSSY 9606 21364637 t miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells SIGNOR-277645 0.2 CAMK2B protein Q13554 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 15980064 t lperfetto 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-217493 0.2 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164629 0.557 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 15208637 t amattioni The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin SIGNOR-126059 0.938 CUL1 protein Q13616 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 SIGNOR-C5 10023660 t lperfetto These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin. SIGNOR-64499 0.598 STK3 protein Q13188 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates phosphorylation -1 BTO:0000007 16930133 t milica In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav SIGNOR-230716 0.834 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 BTO:0000567 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-264482 0.2 okadaic acid chemical CHEBI:44658 ChEBI STK4 protein Q13043 UNIPROT up-regulates 9606 23493077 f gcesareni Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway. SIGNOR-201554 0.8 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 0.308 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 0.8 PLCG1 protein P19174 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni Phosphorylation at Ser-146 by PKCδ increases p21 stability SIGNOR-262962 0.262 GEM protein P55040 UNIPROT CACNB2 protein Q08289 UNIPROT down-regulates activity binding 9606 14701738 t miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261720 0.2 HMOX1 protein P09601 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR form complex binding BTO:0000298 22503972 t Giorgia Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. SIGNOR-260388 0.344 LRRC4B protein Q9NT99 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-264052 0.37 MCM3 protein P25205 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-261673 0.782 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 17311002 t gcesareni However, the same cells were highly sensitive to the irreversible dual-specificity egfr/erbb2 kinase inhibitor hki-272, as were those overexpressing wild-type erbb2. SIGNOR-153318 0.8 ZBTB46 protein Q86UZ6 UNIPROT PTGS1 protein P23219 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 30312731 t miannu ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. SIGNOR-277991 0.2 CYFIP1 protein Q7L576 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-253568 0.905 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 0.2 NSMCE4A protein Q9NXX6 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-265486 0.832 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 0.735 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr566 SLNQEDIyITTESLT 10029 BTO:0000246 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248394 0.295 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 SIGNOR-C110 19293931 t gcesareni In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] SIGNOR-184696 0.579 NBR1 protein Q14596 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni Nbr1 and p62 interact and form oligomers. SIGNOR-184273 0.472 FGF11 protein Q92914 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 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-253418 0.2 UBR5 protein O95071 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase |UBR5 ubiquitinates the acetylated PEPCK1 SIGNOR-267600 0.308 IFNA2 protein P01563 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates quantity by stabilization 9606 22171011 t 2 miannu IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. SIGNOR-240684 0.479 RDH10 protein Q8IZV5 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265120 0.8 SMURF2 protein Q9HAU4 UNIPROT SMAD9 protein O15198 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-193390 0.644 PIP3 smallmolecule CHEBI:16618 ChEBI AKT2 protein P31751 UNIPROT up-regulates activity chemical activation 9606 21779497 t lperfetto When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. SIGNOR-175247 0.8 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263417 0.537 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity binding 9534 BTO:0000298 11278251 t miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  SIGNOR-272942 0.882 ACE protein P12821 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage 9606 11076943 t gcesareni Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide. SIGNOR-253326 0.782 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 0.2 BMP15 protein O95972 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 BTO:0000975 SIGNOR-C29 16446785 t gcesareni Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle. SIGNOR-144098 0.536 IRF2BP1 protein Q8IU81 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 t miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. SIGNOR-224045 0.692 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 0.69 GDNF protein P39905 UNIPROT LAMA3 protein Q16787 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-252175 0.2 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 6239 SIGNOR-C15 17900900 t lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. SIGNOR-219247 0.517 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 SIGNOR-C9 15241418 t llicata We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase SIGNOR-126744 0.746 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 0.878 DPF3 protein Q92784 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270690 0.743 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 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-230761 0.456 acetylsalicylic acid chemical CHEBI:15365 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 11809688 t gcesareni Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects. SIGNOR-114380 0.8 SL-327 chemical CHEBI:92211 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity SIGNOR-244955 0.8 MAOA protein P21397 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-263999 0.8 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101328 0.96 warfarin chemical CHEBI:10033 ChEBI VKORC1 protein Q9BQB6 UNIPROT down-regulates activity chemical inhibition 9606 27941861 t lperfetto Warfarin and vitamin K compete for binding to Phe55 in human VKOR|Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor. SIGNOR-265911 0.8 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 0.2 CDK1 protein P06493 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 t gcesareni We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases , cdc7-dbf4 and the gsk-3 homolog mck1. SIGNOR-200400 0.474 POLG2 protein Q9UHN1 UNIPROT DNA polymerase gamma complex SIGNOR-C378 SIGNOR form complex binding -1 19837034 t lperfetto Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit. SIGNOR-265718 0.715 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 0.362 JAG2 protein Q9Y219 UNIPROT JAG1 protein P78504 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 9315665 f gcesareni Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1. SIGNOR-236888 0.413 IKZF3 protein Q9UKT9 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates activity 10090 BTO:0004731 14718515 f Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos−/− mice with a range of hapten concentrations. SIGNOR-259952 0.7 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 0.503 WDHD1 protein O75717 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates activity binding 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. Significantly, And-1 binds directly to ssDNA and facilitates the association of Claspin with ssDNA. SIGNOR-262665 0.392 TP53 protein P04637 UNIPROT FAS protein P25445 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 9841917 t Nuclear p53 amattioni In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, SIGNOR-62376 0.605 CD38 protein P28907 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide SIGNOR-264253 0.8 P2RY2 protein P41231 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-257233 0.2 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 17609368 t gcesareni 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-228646 0.504 HDAC1 protein Q13547 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 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-222124 0.711 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 BTO:0000452 19318349 t gcesareni PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells. SIGNOR-248075 0.644 MAPK14 protein Q16539 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-264446 0.28 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 0.8 CSF1R protein P07333 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates 9606 24890514 t apalma Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway SIGNOR-255570 0.369 PAH protein P00439 UNIPROT phenylalanine smallmolecule CHEBI:28044 ChEBI down-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-263988 0.8 PPARGC1A protein Q9UBK2 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255055 0.244 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 0.7 MAML1 protein Q92585 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. SIGNOR-84838 0.79 CD40 protein P25942 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000776 18635759 t lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. SIGNOR-179473 0.844 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 0.8 CDK5 protein Q00535 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR form complex binding 9606 11331872 t lperfetto Induced p35 forms a complex with Cdk5 and activates its kinase activity SIGNOR-250683 0.943 NR3C1 protein P04150 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 8878484 t fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. SIGNOR-44376 0.53 PKI-587 chemical CID:44516953 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205986 0.8 KMN network complex SIGNOR-C366 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 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-265215 0.7 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 9606 23074268 t lperfetto it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity. SIGNOR-199162 0.429 IL21 protein Q9HBE4 UNIPROT BCL6 protein P41182 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0000785 22486304 f miannu Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression. SIGNOR-196918 0.397 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 0.2 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 21316371 t gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) SIGNOR-171907 0.34 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2029 NAVDDLGkSALHWAA 9606 17636029 t gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. SIGNOR-156911 0.414 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 0.25 OXGR1 protein Q96P68 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-257243 0.2 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 0.2 APC2 protein O95996 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9601641 t lperfetto 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-227945 0.59 LINC complex complex SIGNOR-C303 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 24481844 f lperfetto The extensive covalent and non-covalent attachments as well as the binding avidity between three KASH domains with three SUN domains are thought to enable the LINC complex to transmit force between the cytoskeleton and the nucleoskeleton SIGNOR-263293 0.7 E2F1 protein Q01094 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 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-240547 0.815 PIP3 smallmolecule CHEBI:16618 ChEBI ZFYVE1 protein Q9HBF4 UNIPROT up-regulates chemical activation 9606 18725538 t gcesareni Dfcp1 contains two fyve domains (thus explaining its pi(3)p binding) SIGNOR-180527 0.8 NR1D1 protein P20393 UNIPROT NR2E3 protein Q9Y5X4 UNIPROT up-regulates 9606 15190009 f gcesareni Our results show that nr1d1 (rev-erb?) Also functions as a transcriptional activator of rod genes in the presence of nr2e3 SIGNOR-125658 0.399 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide chemical CHEBI:91354 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190146 0.8 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 0.563 IL31RA protein Q8NI17 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782 18926762 t gcesareni Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex. SIGNOR-161342 0.497 leucine smallmolecule CHEBI:25017 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-264748 0.7 spermidine smallmolecule CHEBI:16610 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-255553 0.7 PRKCB protein P05771 UNIPROT EEF1A2 protein Q05639 UNIPROT up-regulates activity phosphorylation Ser53 AAEMGKGsFKYAWVL 10090 20923971 t miannu PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein. SIGNOR-263166 0.2 RNF26 protein Q9BY78 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity ubiquitination 9606 25254379 t miannu As a result, knockdown of RNF26 promoted degradation of MITA after viral infection and prevented degradation of IRF3.|In addition, RNF26 could not induce polyubiquitination of MITA (K150R) in in vitro ubiquitination assays (XREF_FIG). SIGNOR-278573 0.2 MARK2 protein Q7KZI7 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates activity phosphorylation 9606 22238344 t miannu MARK2 phosphorylated and activated the cleaved form of PINK1 (DeltaN-PINK1 SIGNOR-278975 0.367 SRF protein P11831 UNIPROT IL6 protein P05231 UNIPROT up-regulates 9606 22225874 t FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. SIGNOR-255966 0.281 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys490 QCPRKVIkMESEEGK 9534 BTO:0000298 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. SIGNOR-270541 0.78 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Thr433 DCDFGDLtPLDF 9606 10428966 t lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. SIGNOR-69780 0.493 RNF135 protein Q8IUD6 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys909 QTLYSKWkDFHFEKI 9606 BTO:0000007 19017631 t miannu Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. SIGNOR-265569 0.764 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 0.7 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 0.406 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74839 0.791 KCNB2 protein Q92953 UNIPROT VAPB protein O95292 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 t lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. SIGNOR-262123 0.2 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 14585074 t lperfetto The fas receptor, upon binding to the fasl, trimerizes SIGNOR-85991 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189978 0.8 DAB2IP protein Q5VWQ8 UNIPROT ZEB1 protein P37275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27858941 f miannu Through inhibition of PI3K–AKT signaling, DAB2IP also represses ZEB1, another CSC determinant. SIGNOR-254772 0.268 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR2 protein P37173 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193778 0.8 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser380 ATLARRDsLQKPGLE 9606 21822051 t lperfetto In the present study, aurora a was demonstrated to phosphorylate lats2 on serine 380 (s380) during mitosistogether, the results suggest that the aurora a-lats1/2-aurora b axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of lats2. SIGNOR-175939 0.38 MEN1 protein O00255 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 11526476 t lperfetto Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner. SIGNOR-217406 0.422 AKT proteinfamily SIGNOR-PF24 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT up-regulates quantity phosphorylation Ser57 HGTGHPEsAGEHALE 9606 BTO:0000007 18280241 t miannu Akt phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo. RanBP3 phosphorylation increases its affinity towards Ran SIGNOR-276150 0.2 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 0.2 PORCN protein Q9H237 UNIPROT WNT3A protein P56704 UNIPROT up-regulates activity palmitoylation Ser209 KCKCHGLsGSCEVKTC 9606 BTO:0000007 20826466 t And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane. SIGNOR-256598 0.7 SRC protein P12931 UNIPROT MMP14 protein P50281 UNIPROT unknown phosphorylation Tyr573 GTPRRLLyCQRSLLD 9606 17389600 t llicata We show that mt1-mmp is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (tyr(573)) and that this phosphorylation requires the kinase src. accordingly, overexpression of a nonphosphorylable mt1-mmp mutant (y573f) blocked sphingosine-1-phosphate-induced migration of human umbilical vein endothelial cells and ht-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells). SIGNOR-154006 0.435 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser491 VPETKGKsFEEIAAE 9534 8626492 t miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. SIGNOR-250049 0.2 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 0.2 HMGB1 protein P09429 UNIPROT HOXD10 protein P28358 UNIPROT up-regulates activity binding -1 8890171 t 2 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. 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-240556 0.292 TNF protein P01375 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 16813528 f lperfetto These observations suggest that tnf-alpha activates p38 map kinase during the inflammatory response at the injured growth plate, and tnf-alpha-p38 signaling seems to be required for marrow mesenchymal cell proliferation and migration at the growth plate injury site and in cell culture. SIGNOR-147369 0.644 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 16049944 t lperfetto Zap-70 is modified by auto-phosphorylation of various tyrosine residues and is activated by specific phosphorylation of the tyrosine residue y-493 SIGNOR-139098 0.2 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 0.2 TGFB2 protein P61812 UNIPROT KRT1 protein P04264 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16258965 f Regulation miannu Immunolocalization of the epithelial marker cytokeratin demonstrates decreased staining by 48 hr after the addition of TGFβ1 or TGFβ2 SIGNOR-251885 0.2 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-181271 0.2 ITCH protein Q96J02 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21093410 t miannu Collectively, our present findings suggest that MDM2 promotes Itch-mediated degradation of p73 through the interaction with Itch in HeLa cells SIGNOR-278699 0.566 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr250 NSCTPITtPELTTPC 9606 20927323 t gcesareni Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e. SIGNOR-168310 0.514 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 0.741 SUPT20H protein Q8NEM7 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269575 0.749 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 0.312 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252850 0.911 PK proteinfamily SIGNOR-PF80 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates activity binding 9606 BTO:0000567 21620138 t PKM2 interacts directly with the HIF-1Œ± subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, SIGNOR-268150 0.389 BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 10712517 t gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors SIGNOR-75652 0.631 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition SIGNOR-209862 0.469 ACACA protein Q13085 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267105 0.8 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 0.2 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190182 0.8 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 0.7 TIMM10 protein P62072 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267701 0.714 NOTCH proteinfamily SIGNOR-PF30 SIGNOR SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 t gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. SIGNOR-254337 0.2 BCL2L1 protein Q07817 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates activity binding 10365962 t lperfetto The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly SIGNOR-249614 0.566 CCT129202 chemical CID:16202152 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190877 0.8 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 0.635 TNFRSF17 protein Q02223 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 10903733 f inferred from 70% of family members miannu Overexpression of bcma activates the p38 mapk SIGNOR-269917 0.265 CREB1 protein P16220 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000158 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-253798 0.418 IL13 protein P35225 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1. SIGNOR-100750 0.853 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 19350555 t miannu PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src). SIGNOR-277086 0.542 MAPK3 protein P27361 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 t Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. SIGNOR-269086 0.247 PRKACA protein P17612 UNIPROT APOBEC3G protein Q9HC16 UNIPROT up-regulates phosphorylation Thr32 PILSRRNtVWLCYEV 9606 18836454 t llicata Here we show that pka binds and specifically phosphorylates a3g at thr32 in vitro and in vivo. This phosphorylation event reduces the binding of a3g to vif and its subsequent ubiquitination and degradation, and thus promotes a3g antiviral activity. SIGNOR-181526 0.324 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 0.395 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 0.8 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 0.336 SEC62 protein Q99442 UNIPROT Protein_translocation phenotype SIGNOR-PH176 SIGNOR up-regulates 22375059 f lperfetto We demonstrated, with a similar knockdown approach, a precursor-specific involvement of mammalian Sec63 in the initial phase of co-translational protein transport into the ER. SIGNOR-265281 0.7 DOK1 protein Q99704 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257675 0.315 TFEB protein P19484 UNIPROT GALNS protein P34059 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276538 0.289 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent. SIGNOR-268787 0.8 C5AR1 protein P21730 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. SIGNOR-263460 0.7 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ITK protein Q08881 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262236 0.8 RORB protein Q92753 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18418469 t miannu RORβ and RORγ are also able to induce Bmal1 activity; however, RORα4 appears the most effective in inducing this activity. The ROREs in the Bmal1 promoter also bind ROR receptors. Overexpression of RORα1 and RORα4 induces Bmal1-promoter activity by interacting with these ROREs SIGNOR-266852 0.478 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248610 0.494 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 0.323 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133820 0.819 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249345 0.739 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 0.833 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates 9606 12447388 f miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95918 0.566 FASN protein P49327 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 9606 20373869 f lperfetto Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis SIGNOR-242874 0.7 INPP4B protein O15327 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity dephosphorylation 9606 26411369 t lperfetto In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.|INPP4B downregulates PTEN in colon cancer cells. SIGNOR-277018 0.632 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 9606 21620960 t lperfetto Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252866 0.765 CD38 protein P28907 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity relocalization 10090 17287729 f lperfetto CD38 is critical for social behaviour by regulating oxytocin secretion|Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. SIGNOR-268544 0.365 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 0.484 ELF4 protein Q99607 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19380490 f miannu We found that elf4/mef activates mdm2 expression SIGNOR-185490 0.383 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 0.448 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1437 RYPDSYEsMSEPPIA -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-262907 0.701 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 20457810 f fspada Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. SIGNOR-209965 0.381 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 0.813 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 22298955 t lperfetto Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 SIGNOR-217709 0.684 EEF1A1 protein P68104 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-269393 0.7 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 0.861 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 0.636 BFAR protein Q9NZS9 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates binding 9606 BTO:0000093 11733517 t gcesareni We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2 SIGNOR-112585 0.37 Early macropinosomes phenotype SIGNOR-PH228 SIGNOR Late macropinosomes phenotype SIGNOR-PH229 SIGNOR up-regulates 9606 39000072 f miannu The early macropinosomes continue to mature into late macropinosomes, which fuse with lysosomes and degrade their cargos. SIGNOR-277789 0.7 MCUB protein Q9NWR8 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-270863 0.2 PFKFB4 protein Q16877 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI down-regulates quantity chemical modification -1 30553771 t PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species SIGNOR-267272 0.8 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 0.2 GDNF protein P39905 UNIPROT CLU protein P10909 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252187 0.261 H3-3A protein P84243 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263876 0.2 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194334 0.8 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259240 0.8 HDAC3 protein O15379 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275662 0.257 GRIK2 protein Q13002 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268273 0.8 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 0.7 KDM4B protein O94953 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 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-263734 0.2 RBM8A protein Q9Y5S9 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265242 0.918 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244303 0.2 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT unknown phosphorylation Ser103 RGLKRSLsEMEIGMV 9606 BTO:0000567 10318869 t llicata Mk2 phosphorylates srf in vitro at ser-103 SIGNOR-67448 0.584 SMAD3 protein P84022 UNIPROT CEBPA protein P49715 UNIPROT down-regulates activity binding 10090 12524424 t gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters SIGNOR-241924 0.375 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor. SIGNOR-104545 0.313 NCS1 protein P62166 UNIPROT GRK2 protein P25098 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000938 12351722 t miannu Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. SIGNOR-263965 0.2 LSM-1131 chemical CHEBI:91398 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189873 0.8 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 10548111 t amattioni The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7). SIGNOR-71954 0.939 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 21454675 t gcesareni Receptor-type protein tyrosine phosphatase beta (rptp-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (hgfr/met) function. SIGNOR-173004 0.364 EPAS1 protein Q99814 UNIPROT PTPRZ1 protein P23471 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15833863 f miannu A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases. SIGNOR-264333 0.262 CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18177723 f andrea cerquone perpetuini Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells. SIGNOR-255412 0.7 RPS6KA3 protein P51812 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-184595 0.385 SRMS protein Q9H3Y6 UNIPROT DOK1 protein Q99704 UNIPROT unknown phosphorylation 9606 BTO:0000007 23822091 t lperfetto These data indicate that ectopically‐expressed GFP‐SRMS interacts with and mediates the phosphorylation of overexpressed GFP‐Dok1. SIGNOR-264569 0.414 PKI-587 chemical CID:44516953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205989 0.8 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0000776 8657103 t lperfetto Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. SIGNOR-246572 0.775 MDH2 protein P40926 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266284 0.8 CBX1 protein P83916 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264493 0.2 PRKACA protein P17612 UNIPROT 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-275630 0.253 STK3 protein Q13188 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity phosphorylation Thr622 KEGGVTFtWVEKDIS -1 35722967 t miannu Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation. SIGNOR-277599 0.2 HECTD3 protein Q5T447 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000007 23358872 t miannu HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it.  SIGNOR-272096 0.366 AGTR1 protein P30556 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9606 BTO:0000007 20181817 t The angiotensin II type 1 receptor (AT1 R) is a G q/11-coupled G protein-coupled receptor that is widely expressed in multiple tissues, including vascular smooth muscle cells, brain, and kidney. SIGNOR-278125 0.512 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 0.8 GSN protein P06396 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. SIGNOR-261835 0.7 SMC3 protein Q9UQE7 UNIPROT MXI1 protein P50539 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-241223 0.403 WWTR1 protein Q9GZV5 UNIPROT TEAD4 protein Q15561 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-201459 0.869 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 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-248631 0.748 AVEN protein Q9NQS1 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity binding -1 18571408 t miannu These data suggest that Aven overexpression can activate ATM and that Aven phosphorylation in a positive feedback loop enforces Aven activity, making it a more potent ATM activator. SIGNOR-262638 0.381 CD27 protein P26842 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12324477 f gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. SIGNOR-93317 0.2 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 0.472 tamoxifen citrate chemical CHEBI:9397 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000150 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-259301 0.8 PARD6A protein Q9NPB6 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 9606 BTO:0000007 22544755 t lperfetto The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains. SIGNOR-227489 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-262960 0.2 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 0.986 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 0.8 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 0.79 C5 protein P01031 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 cleavage:Arg751 HKDMQLGrLHMKTLL 30552328 t complement C5b fragment: PRO_0000005989 lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263440 0.621 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 19143636 t lperfetto Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. SIGNOR-209859 0.384 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 t lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 0.942 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 0.502 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268387 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR HK2 protein P52789 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000192 31435020 t K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization SIGNOR-259985 0.2 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 0.772 CFH protein P08603 UNIPROT CFI protein P05156 UNIPROT up-regulates activity binding 9606 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-263490 0.92 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 12435421 t miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly SIGNOR-250008 0.433 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 0.279 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164663 0.2 Tosedostat chemical CID:15547703 PUBCHEM ANPEP protein P15144 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207372 0.8 PRKCD protein Q05655 UNIPROT CNTNAP1 protein P78357 UNIPROT down-regulates activity phosphorylation 9606 19632305 t miannu Inhibition of PKCdelta increased p190 activity, while PKCdelta overexpression diminished p190 activity.|We further show that PKC\u03b4 was able to phosphorylate and bind distinct domains of p190. SIGNOR-279260 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262221 0.8 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 BTO:0000782 12151396 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk SIGNOR-91059 0.352 WDR83 protein Q9BRX9 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15118098 t lperfetto 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-244964 0.533 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 0.7 KPNA4 protein O00629 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. SIGNOR-165314 0.287 SMAD2/SMAD4 complex SIGNOR-C8 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-256287 0.604 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression 9606 17705188 f lperfetto Inflammatory stimuli can activate IkappaB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF-kappaB), which influences gene expression of cyclooxygenase-2 (Cox-2) along with other transcription factors. SIGNOR-260262 0.364 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser739 GSIDMVDsPQLATLA 9606 BTO:0000938 16923168 t The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. SIGNOR-148978 0.451 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr741 NLYSGDYyRIQGRAV 9606 16186108 t gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. SIGNOR-140767 0.38 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 0.281 CASP12 protein Q6UXS9 UNIPROT CASP9 protein P55211 UNIPROT up-regulates cleavage 9606 BTO:0000222 12097332 t gcesareni Caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. Results suggest that caspase-12 can activate caspase-9 without involvement of cytochromec. SIGNOR-90318 0.2 CKM complex complex SIGNOR-C406 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 15546612 t gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-273153 0.384 CDK2 protein P24941 UNIPROT ATRIP protein Q8WXE1 UNIPROT unknown phosphorylation Ser239 VIKPEACsPQFGKTS 9606 17638878 t lperfetto Two novel phosphorylation sites on atrip were identified, s224 and s239 SIGNOR-156932 0.579 PLK1 protein P53350 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates activity phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 BTO:0000567 21642957 t done miannu We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1. SIGNOR-273888 0.611 EGFR protein P00533 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR up-regulates activity phosphorylation 9606 15284024 t 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-252088 0.631 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 0.359 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 0.748 clomipramine chemical CHEBI:47780 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 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-258875 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities. SIGNOR-105758 0.2 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258305 0.8 3-methyladenine chemical CHEBI:38635 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205636 0.8 USO1 protein O60763 UNIPROT GOLGB1 protein Q14789 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-261237 0.84 ABCA7 protein Q8IZY2 UNIPROT APP protein P05067 UNIPROT down-regulates quantity relocalization 9606 BTO:0000142 27472885 f miannu Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD. SIGNOR-265176 0.406 RET protein P07949 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 27994058 t miannu In detail, RET and PTC3 induced STAT1 overexpression and phosphorylation at Ser 727 and Tyr 701. SIGNOR-279277 0.275 CDK4 protein P11802 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates phosphorylation Ser632 LVVSRNLsPPNCTEL 9606 BTO:0000150 SIGNOR-C18 17334399 t lperfetto In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo. SIGNOR-153450 0.665 MYBBP1A protein Q9BQG0 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268821 0.484 CAMK2D protein Q13557 UNIPROT ANKRD28 protein O15084 UNIPROT down-regulates activity phosphorylation Ser1011 TNTSKTVsFEALPIM -1 17023142 t lperfetto We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K SIGNOR-264793 0.2 GABA-B receptor complex SIGNOR-C336 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 9872316 f brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. SIGNOR-263794 0.7 BMP4 protein P12644 UNIPROT MRTFA protein Q969V6 UNIPROT up-regulates 9606 21673106 f gcesareni These results demonstrate that mrtf-a is essential for the bmp4-mediated induction of pri-mir-143/145 and mature mir-143/145, whereas tgf- -mediated induction of mir-143/145 requires myocd. Mrtf-a is primarily localized in the cytoplasm in unstimulated cells;upon stimulation with bmp4, mrtf-a translocates into the nucleus to promote changes in gene expression. SIGNOR-174124 0.2 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys709 QTLESFFkPLTH 9606 21791603 t miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). SIGNOR-272733 0.581 GCC1 protein Q96CN9 UNIPROT ITSN1 protein Q15811 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 30540523 t Giulio GFP-GCC88 was immunoprecipitated by both the short and long form of ITSN-1 but not with FLAG-Rheb (Figure 4A). These data demonstrate that both GCC88 and ITSN-1 are part of a complex. We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A). SIGNOR-260600 0.2 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser197 TKSIYTRsVIDPVPA -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250226 0.2 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258137 0.8 L3MBTL1 protein Q9Y468 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity binding 9606 29018219 t lperfetto L3MBTL1, a tumor suppressor with high affinity for H4K20me2, can block 53BP1 binding at DSBs SIGNOR-262059 0.404 URB597 chemical CID:1383884 PUBCHEM FAAH protein O00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207615 0.8 GUCA2A protein Q02747 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-78096 0.771 NVP-ADW742 chemical CID:9825149 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194883 0.8 ERC1 protein Q8IUD2 UNIPROT CHUK protein O15111 UNIPROT up-regulates binding 9606 SIGNOR-C14 15218148 t miannu Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation. SIGNOR-126430 0.59 MAOB protein P27338 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264002 0.8 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone chemical CHEBI:91454 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190443 0.8 TTC19 protein Q6DKK2 UNIPROT CHMP4B protein Q9H444 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C379 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-265541 0.417 NR3C1 protein P04150 UNIPROT IRAK3 protein Q9Y616 UNIPROT up-regulates quantity transcriptional regulation 9606 25585690 t We show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter SIGNOR-259287 0.36 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Ser742 GEKSFRRsVVGTPAY 18692497 t lperfetto The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. SIGNOR-275925 0.2 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 0.271 GNA13 protein Q14344 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 BTO:0000944 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-256519 0.772 CDK5 protein Q00535 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Thr235 YEKDDKLtPKIGFPW 9606 BTO:0000971 12769842 t llicata Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype. SIGNOR-250665 0.464 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270840 0.2 NOTCH1 protein P46531 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001454 10933396 f gcesareni Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression SIGNOR-80333 0.416 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 BTO:0000130 14499342 t lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. SIGNOR-118044 0.769 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 0.583 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser7 sSSSYRRM -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248886 0.284 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Thr194 FPKTSSAtPQETLIS -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265961 0.515 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 0.495 CENPO protein Q9BU64 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265209 0.827 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 0.8 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 0.474 SCRIB protein Q14160 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-270900 0.449 ADL-5859 chemical CID:46931003 PUBCHEM OPRD1 protein P41143 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189278 0.8 PRKD1 protein Q15139 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates activity phosphorylation Ser801 SSLPRPMsSRSFPRS 9606 BTO:0000007 20881056 t miannu Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. Phosphorylation at this site was significantly increased in response to serum and epidermal growth factor stimulation.We confirmed previous studies showing that PC2 mediated Ca2+ release from the ER can be stimulated by ATP.Phosphorylation at Ser801 seems to be permissive for this activity without altering the subcellular localization nor homophilic and heterophilic (with PC1) interactions of wild-type PC2. SIGNOR-259829 0.458 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 0.746 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 0.755 LRFN2 protein Q9ULH4 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-264099 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270420 0.8 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser312 SYLSQMTsPSIHSTT 9606 19801668 t llicata In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation. SIGNOR-188347 0.565 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 0.316 MMP19 protein Q99542 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-272363 0.7 TCF12 protein Q99081 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f miannu Hebalt positively regulates t-cell genes, such as pt_ and notch3 SIGNOR-197517 0.257 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 t miannu Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687 SIGNOR-168392 0.345 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 0.7 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 0.727 maraviroc chemical CHEBI:63608 ChEBI CCR5 protein P51681 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194248 0.8 PAX3 protein P23760 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-222235 0.422 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 0.2 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 0.2 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 0.686 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 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-134537 0.745 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB2 protein Q00722 UNIPROT up-regulates 23994464 t apalma However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits SIGNOR-255015 0.547 RNF139 protein Q8WU17 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  SIGNOR-271956 0.436 EZH2 protein Q15910 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 22808286 f miannu EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. SIGNOR-254144 0.405 RANBP9 protein Q96S59 UNIPROT DYRK1B protein Q9Y463 UNIPROT down-regulates activity binding 9606 BTO:0000007 14500717 t llicata Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M. SIGNOR-238008 0.418 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206088 0.8 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 21423276 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-172917 0.8 TWIST2 protein Q8WVJ9 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-255496 0.2 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2 protein Q05397 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206067 0.8 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6. SIGNOR-199650 0.292 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 0.781 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 0.8 NR3C1 protein P04150 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity transcriptional regulation 10116 15793248 f We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor. SIGNOR-255926 0.46 NOTCH1 protein P46531 UNIPROT HEYL protein Q9NQ87 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni These data confirm heyl as a notch1 target gene that is likely involved in somite formation and patterning. SIGNOR-83399 0.61 PRKG1 protein Q13976 UNIPROT TRPC6 protein Q9Y210 UNIPROT down-regulates activity phosphorylation Thr70 RLAHRRQtVLREKGR -1 19961855 t miannu PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q).  SIGNOR-276272 0.491 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 0.287 BAZ2B protein Q9UIF8 UNIPROT H3C15 protein Q71DI3 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-266623 0.2 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR MYC protein P01106 UNIPROT up-regulates activity 9606 19855079 t apalma We demonstrate that in addition to blocking myeloid differentiation, PLZF-RARα also promotes proliferation/self-renewal via the aberrant regulation of cell cycle–associated genes such as c-Myc, providing a basis for studying the aberrant response of this leukemia subtype to retinoic acid. SIGNOR-256374 0.2 AKT1 protein P31749 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 19526459 t llicata Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1. SIGNOR-252525 0.363 IKBKE protein Q14164 UNIPROT TRAF3IP2 protein O43734 UNIPROT up-regulates activity phosphorylation Ser328 KVILNYPsPWDHEER 9606 21822257 t miannu IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function. SIGNOR-262883 0.416 (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 0.8 NUAK1 protein O60285 UNIPROT MAPT protein P10636 UNIPROT up-regulates quantity phosphorylation Ser673 RVQSKIGsLDNITHV 9606 27720485 t miannu These results confirm that the effect of Nuak1 over tau levels is mainly due to tau phosphorylation at Ser356 by Nuak1.|Western blot analysis revealed that a 50% reduction in Nuak1 was sufficient to decrease tau levels in the brain (XREF_FIG). SIGNOR-279306 0.249 GPR119 protein Q8TDV5 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-256911 0.25 triptorelin chemical CHEBI:63633 ChEBI GNRH1 protein P01148 UNIPROT up-regulates activity chemical activation 9606 22416801 t miannu The comparative effects of degarelix and GnRH agonists were assessed in two studies in a rat model of prostate cancer.14 In a 2‐month study, rats receiving the GnRH agonist, triptorelin (0.5 mg/kg daily), experienced an initial testosterone surge, followed by suppression to castration levels by day 28, which was maintained for the remainder of the study. SIGNOR-259158 0.8 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 10090 BTO:0000887 16936075 t lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) SIGNOR-217827 0.701 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation -1 16226275 t inferred from 70% family members lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-270111 0.2 ESR1 protein P03372 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16169518 t gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. SIGNOR-252675 0.662 RUNX1 protein Q01196 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29958106 t miannu RUNX1 represses MYC expression through direct binding at three downstream enhancer elements SIGNOR-260093 0.337 NDUFA11 protein Q86Y39 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5) SIGNOR-262142 0.809 CERS1 protein P27544 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273993 0.8 PDCD1 protein Q15116 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 28286692 f Barakat Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. SIGNOR-275413 0.7 NEK2 protein P51955 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 30968157 t miannu NEK2 silencing reduced the phosphorylation of beta-catenin at Ser33 and Ser37, but did not decrease the level of total beta-catenin.|NEK2 slightly decreased the level of total beta-catenin (XREF_FIG). SIGNOR-278172 0.469 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 0.8 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 0.883 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 0.274 AKT proteinfamily SIGNOR-PF24 SIGNOR PRPH protein P41219 UNIPROT up-regulates activity phosphorylation Ser59 SSSVRLGsFRSPRAG 9606 BTO:0000007 17569669 t miannu Here we demonstrate that peripherin, which is a peripheral nervous system neuron-specific intermediate filament protein, is a novel Akt substrate, and that Ser66 of peripherin is the phosphorylation site. Peripherin phosphorylation is apparently induced in motor neurons after nerve injury, suggesting that the Akt-mediated peripherin phosphorylation may play a role in motor nerve regeneration. SIGNOR-262627 0.2 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 0.744 SLC44A2 protein Q8IWA5 UNIPROT choline smallmolecule CHEBI:15354 ChEBI up-regulates activity relocalization 9606 21367571 t lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it SIGNOR-260409 0.8 HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK1 protein Q9Y566 UNIPROT up-regulates activity binding 9606 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264698 0.2 SOCS1 protein O15524 UNIPROT VAV1 protein P15498 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0000298 10747851 t miannu SOCS1 stimulates the polyubiquitination of VAV proteins in vivo, which was stabilized by proteasomal inhibitors. These results suggest that SOCS1 programs VAV degradation by acting as a substrate-specific recognition component of a VCB-like ubiquitin ligase complex. SIGNOR-272559 0.598 PRKACA protein P17612 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS -1 12853467 t miannu PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚  SIGNOR-250025 0.444 NR3C1 protein P04150 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8639160 t gcesareni We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins SIGNOR-251679 0.743 CARS1 protein P49589 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270805 0.8 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61552 0.942 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT up-regulates activity phosphorylation Ser120 RAKEVRGsGSYEYPV 9606 BTO:0003477 10728420 t miannu Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345 SIGNOR-250357 0.307 RACK1 protein P63244 UNIPROT TRPM6 protein Q9BX84 UNIPROT down-regulates activity binding 9606 BTO:0000007 18258429 t Manara We identified RACK1 as the first TRPM6-associated protein and demonstrated that RACK1 inhibits TRPM6 channel activity depending on the phosphorylation state T1851 in the α-kinase domain. SIGNOR-260921 0.2 glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). SIGNOR-268136 0.8 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 0.819 PGR protein P06401 UNIPROT KLK4 protein Q9Y5K2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 19147544 f miannu we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. SIGNOR-254913 0.258 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 0.806 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr393 RLMTGDTyTAHAGAK 9534 BTO:0004055 11163214 t lperfetto Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated. SIGNOR-235568 0.439 SIX4 protein Q9UIU6 UNIPROT UBA52 protein P62987 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-62178 0.2 BMP10 protein O95393 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 t acerquone Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis SIGNOR-150201 0.709 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 t lperfetto Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation. SIGNOR-244784 0.2 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 0.337 apigenin chemical CHEBI:18388 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189802 0.8 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 22378047 f IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype SIGNOR-254515 0.79 CWC27 protein Q6UX04 UNIPROT Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11991638 f Purification and characterization of native pliceosomes suitable for three-dimensional structural analysis SIGNOR-261148 0.7 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 20395206 t gcesareni With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation. SIGNOR-164804 0.887 DZIP3 protein Q86Y13 UNIPROT H2AC7 protein P20671 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271753 0.2 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 0.728 HES1 protein Q14469 UNIPROT ATOH1 protein Q92858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265144 0.471 MDGA2 protein Q7Z553 UNIPROT CDKN1A protein P38936 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-264242 0.2 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 0.565 KLF11 protein O14901 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 10207080 f Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. SIGNOR-251828 0.2 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t 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-143696 0.637 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 0.7 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176757 0.8 MAPK13 protein O15264 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-263084 0.419 PTMA protein P06454 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000567 12522243 t PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. SIGNOR-259079 0.364 LEPR protein P48357 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0001282 18718905 t miannu Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. SIGNOR-263491 0.774 LSM7 protein Q9UK45 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270647 0.805 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 t gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 0.8 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 8302603 t lperfetto Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation SIGNOR-37727 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser495 KTMIRKRsFGNPFEG 9606 22778263 t lperfetto Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity SIGNOR-198150 0.2 LYN protein P07948 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262676 0.2 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 0.458 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. SIGNOR-191847 0.595 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 t lperfetto The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. SIGNOR-227881 0.895 MYB protein P10242 UNIPROT GSTM1 protein P09488 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14576818 t Functional analysis of the GSTM1 promoter using reporter assays indicated that both the DNA binding and transactivation domains of Myb were required for transcriptional activation SIGNOR-253975 0.2 STK11 protein Q15831 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity phosphorylation Thr77 KCVTIQRtLDGRLQV 9606 20974850 t miannu LKB1 inhibits the DNA binding and the transcriptional activity of Smad4.|We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr 77 of its DNA-binding domain. SIGNOR-278193 0.631 SP3 protein Q02447 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-255203 0.2 HIP1 protein O00291 UNIPROT REST protein Q13127 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21832040 f miannu HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). SIGNOR-255076 0.2 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275873 0.2 chloroquine chemical CHEBI:3638 ChEBI TNF protein P01375 UNIPROT down-regulates quantity 9606 32283152 f miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. SIGNOR-260853 0.8 AMHR2 protein Q16671 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 14746809 t gcesareni See table2 SIGNOR-121596 0.43 CREB1 protein P16220 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000142 32603820 t miannu Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF. SIGNOR-265062 0.488 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 0.365 CDK1 protein P06493 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation 9606 29971233 t miannu Cdk1 phosphorylates Cdc20 to negatively regulate its ability to bind and activate the APC/C. SIGNOR-279321 0.935 4-Iodo-3-nitrobenzamide chemical CID:9796068 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193474 0.8 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 0.345 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser899 RSKKRKGsDDAPYSP 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-264511 0.2 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219349 0.718 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000567 12356755 t gcesareni Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression. SIGNOR-93873 0.805 RAF1 protein P04049 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 11427728 t gcesareni Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo. SIGNOR-109023 0.395 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104088 0.2 citrate(3-) smallmolecule CHEBI:16947 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267100 0.8 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 0.2 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 BTO:0001938 11157749 t gcesareni When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity SIGNOR-104656 0.849 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 0.729 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 t lperfetto These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. SIGNOR-167548 0.296 arecoline chemical CHEBI:2814 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258641 0.8 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 0.2 RUNX2 protein Q13950 UNIPROT TNFSF11 protein O14788 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-107242 0.474 RIT1 protein Q92963 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 10090 BTO:0000944 23791108 t It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development. SIGNOR-251650 0.55 FHIT protein P49789 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159870 0.269 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 18570871 t gcesareni Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy. SIGNOR-179092 0.582 PPM1G protein O15355 UNIPROT SRSF3 protein P84103 UNIPROT down-regulates activity dephosphorylation 9606 34290239 t miannu Here, we found that the PPM1G regulated SRSF3, and high levels of PPM1G decreased SRSF3 activity in HCC cells.|PPM1G interacted with SRSF3 and dephosphorylated SRSF3. SIGNOR-277048 0.2 PRKD1 protein Q15139 UNIPROT TLR5 protein O60602 UNIPROT up-regulates phosphorylation Ser805 YQLMKHQsIRGFVQK 9606 BTO:0002181 17442957 t lperfetto Pkd phosphorylated the tlr5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in hek 293t cell-derived tlr5 was identified by mass spectrometry. These results demonstrate that both pkd1 and pkd2 are required for inflammatory responses following tlr2, tlr4, or tlr5 activation, although pkd1 is more strongly involved SIGNOR-154473 0.353 CAMK2A protein Q9UQM7 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2426 ASGDRPPsVSSVHSE 9606 22888005 t lperfetto We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. SIGNOR-191773 0.2 IL21R protein Q9HBE5 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 t gcesareni Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5 SIGNOR-90269 0.558 CDK4 protein P11802 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176524 0.28 Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity precursor of 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-268124 0.8 IRF1 protein P10914 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22291912 f miannu SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. SIGNOR-254494 0.31 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr531 NTTGSDNtDTEGS 9606 BTO:0000567 17936701 t PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2 SIGNOR-262290 0.346 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C3 18439900 t lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK SIGNOR-263045 0.693 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 0.92 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser15 FSLLRGPsWDPFRDW -1 8774846 t miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) SIGNOR-250159 0.685 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 0.2 MEF2A protein Q02078 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54086 0.742 PIK3C3 protein Q8NEB9 UNIPROT 1-phosphatidyl-1D-myo-inositol 3-phosphate smallmolecule CHEBI:17283 ChEBI up-regulates chemical modification 9606 8999962 t gcesareni Vps34p phosphorylates phosphatidylinositol (ptdins) at the 3?-Position of the inositol ring, but not ptdins. SIGNOR-45606 0.8 IKBKB protein O14920 UNIPROT RBFOX2 protein O43251 UNIPROT up-regulates activity phosphorylation 9606 20686657 t miannu Phosphorylation of RTA by IKKbeta increases RTA transcriptional activity and consequently viral mRNA production. SIGNOR-279336 0.2 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 0.619 AKT1 protein P31749 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t llicata Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro SIGNOR-184922 0.2 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 0.457 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp317 VSGISLLdNSNASVW 9606 BTO:0000567 11815631 t Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage SIGNOR-260602 0.396 GSK3B protein P49841 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity phosphorylation 9606 27572267 t miannu Together, the results suggest that GSK3\u03b2 binds and phosphorylates the non-glycosylated PD-L1.|We show that glycogen synthase kinase 3\u03b2 (GSK3\u03b2) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by \u03b2-TrCP. SIGNOR-279047 0.307 PRKG2 protein Q13237 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-249080 0.525 PDPK1 protein O15530 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t gcesareni The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma) SIGNOR-55937 0.651 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 0.506 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190245 0.8 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 0.502 CKM complex complex SIGNOR-C406 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates activity phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 t lperfetto Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation. SIGNOR-273138 0.362 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR1 protein P21453 UNIPROT up-regulates chemical activation 9606 16794003 t gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq SIGNOR-147227 0.8 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22387692 f lperfetto The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. SIGNOR-253705 0.646 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser105 TGAGAAGsPAQQHAH 9606 BTO:0000567 26183396 t miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. SIGNOR-276927 0.258 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation./Phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163780 0.274 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-18237 0.506 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22378047 t lperfetto STAT6 coordinates and synergizes with both PPAR? and KrŸppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function. SIGNOR-249568 0.345 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT up-regulates activity phosphorylation Tyr1141 SKKTFASyMPQFQTC 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263494 0.774 PKC proteinfamily SIGNOR-PF53 SIGNOR NOXO1 protein Q8NFA2 UNIPROT up-regulates activity phosphorylation Ser159 SRAAGRLsIHSLEAQ 9606 28336130 t lperfetto Importantly, the constitutive activity of NoxO1 can be modulated. NoxO1 phosphorylation by PKC at Ser154 doubles its binding ability to NoxA1, which in turn acts as a molecular switch, allowing optimal interaction of NoxO1 with p22phox SIGNOR-264728 0.2 TP53 protein P04637 UNIPROT OGG1 protein O15527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16293709 t miannu Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1. SIGNOR-255440 0.429 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 22575959 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane. SIGNOR-197420 0.656 IL1RN protein P18510 UNIPROT IL1R1 protein P14778 UNIPROT down-regulates activity binding 9606 2876877 t Gianni Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β SIGNOR-262302 0.897 TP53RK protein Q96S44 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17712528 t gcesareni The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15. SIGNOR-157471 0.76 TAK-960 chemical CID:53357478 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207200 0.8 dabigatran chemical CHEBI:70752 ChEBI F2 protein P00734 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190314 0.8 MEF2C protein Q06413 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates -1 23001426 f Luana  In brain, MEF2C is essential for early neurogenesis, neuronal migration, and differentiation.  SIGNOR-265800 0.7 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001583 21873430 t miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. SIGNOR-276356 0.435 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 0.489 IL20RB protein Q6UXL0 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000782;BTO:0000876 12941475 f gcesareni Il-20 induces cheratin proliferation and stat-3 signal transduction pathway SIGNOR-86305 0.511 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 0.2 ATF4 protein P18848 UNIPROT DDIT4 protein Q9NX09 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19439225 f lperfetto We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress. SIGNOR-253726 0.414 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 0.246 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 0.2 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 0.2 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 0.25 KAT2A protein Q92830 UNIPROT SLC44A2 protein Q8IWA5 UNIPROT up-regulates quantity 9606 BTO:0003065 21367571 f lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it SIGNOR-260408 0.2 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 0.2 CASP8 protein Q14790 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-261752 0.332 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 16530044 t gcesareni Maml-1 is preassociated with other components of the transcriptional machinery, such as p300 SIGNOR-145057 0.651 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 10368279 f gcesareni Pai-1 is the physiological inhibitor of the fibrinolytic pathway SIGNOR-68481 0.7 873837-23-1 chemical CID:46930994 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190467 0.8 CD28 protein P10747 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000782 18006698 t gcesareni Cd28 can bind directly to pi3k by a well-characterized ymnm binding motif in its cytoplasmic domain. SIGNOR-159322 0.368 FOXL2 protein P58012 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2 SIGNOR-256643 0.7 P4HA2 protein O15460 UNIPROT Collagen proteinfamily SIGNOR-PF103 SIGNOR up-regulates quantity by stabilization hydroxylation 9606 9211872 t miannu Prolyl 4-hydroxylase (proline hydroxylase, EC 1.14.11.2) catalyzes the hydroxylation of proline in -Xaa-Pro-Gly- triplets in collagens and other proteins with collagen-like sequences. The enzyme plays a central role in the synthesis of all collagens, as the 4-hydroxyproline residues formed in the reaction are essential for the folding of the newly synthesized collagen polypeptide chains into triple helical molecules.  SIGNOR-269733 0.2 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser568 SSRRRRSsSTAPPTS 9606 16513649 t llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization SIGNOR-145040 0.2 DLGAP5 protein Q15398 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264598 0.448 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 0.773 GNAI1 protein P63096 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 t TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation SIGNOR-256491 0.2 MAPK3 protein P27361 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity by destabilization phosphorylation Ser277 ASPGSLHsPQQLAEE 10090 BTO:0001077 11466319 t miannu  The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.  SIGNOR-275978 0.41 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 0.416 NOTCH proteinfamily SIGNOR-PF30 SIGNOR IL7R protein P16871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-254345 0.2 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 0.507 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT up-regulates phosphorylation Tyr685 LDARPSLyAQVQKPP 9606 BTO:0000975 16909109 t llicata In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq. SIGNOR-148818 0.567 CUDC-907 chemical CID:54575456 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191212 0.8 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 0.39 KDM5A protein P29375 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 7227 BTO:0000782 20231316 t lperfetto In this study, we show that the histone demethylase kdm5a associated with rbp-j protein and is essential for notch/rbp-j target gene silencing in vitro. SIGNOR-219250 0.385 MYC protein P01106 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 17785433 t inferred from family member 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-270270 0.452 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 0.2 carfilzomib chemical CHEBI:65347 ChEBI PSMB2 protein P49721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 t miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. SIGNOR-259310 0.8 AGTR1 protein P30556 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 21289285 t gcesareni These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction. SIGNOR-171763 0.434 ECM stimulus SIGNOR-ST20 SIGNOR Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259042 0.7 ADORA2A protein P29274 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256766 0.3 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 0.834 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0000399 10706854 t Activation of ERK2 and p38 by eotaxin is mediated through CCR3. SIGNOR-256092 0.248 AT-406 chemical CID:25022340 PUBCHEM BIRC2 protein Q13490 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189954 0.8 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 0.491 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 0.553 GSK3B protein P49841 UNIPROT FBXO4 protein Q9UKT5 UNIPROT up-regulates phosphorylation Ser12 EPRSGTNsPPPPFSD 9606 21242966 t lperfetto Gsk3beta-mediated phosphorylation of fbx4 ser12 during the g1/s transition regulates fbx4 dimerization, which in turn governs fbx4-driven e3 ligase activity. SIGNOR-171648 0.2 icariin chemical CHEBI:78420 ChEBI PDE5A protein O76074 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193363 0.8 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 0.773 JUN protein P05412 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 10369069 f miannu Co-transfection of WT cells with a c-jun expression vector and either of the AP-1 luciferase constructs demonstrated that c-jun could activate gene expression from both the consensus and the MDR1 AP-1 sites in a dose dependent manner. SIGNOR-254534 0.344 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2K protein P61086 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271333 0.845 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 24697349 t Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades. SIGNOR-267725 0.923 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-146672 0.26 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 0.291 HDAC5 protein Q9UQL6 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 11062529 t gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. SIGNOR-84026 0.696 RELA protein Q04206 UNIPROT MET protein P08581 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0002895 19530226 t gcesareni Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival. SIGNOR-241929 0.25 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 0.895 PLK1 protein P53350 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Thr37 SDAKLEPtNVQTVTC 9606 21041660 t lperfetto Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression. SIGNOR-169184 0.566 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 8642285 t irozzo Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant.These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. SIGNOR-255813 0.2 PCNA protein P12004 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR up-regulates activity binding 9534 BTO:0004055 12930972 t lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). SIGNOR-265512 0.576 AURKA protein O14965 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 25217103 t miannu In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic \u03b2-catenin expression in esophageal squamous cell carcinoma tissues.|We also demonstrate for the first time that Aurora-A directly interacts with \u03b2-catenin and phosphorylates \u03b2-catenin at Ser552 and Ser675. SIGNOR-278469 0.346 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17671233 f irozzo C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment.Transcriptional induction of PU.1 by C/EBPα may play a role in myeloid lineage specification. SIGNOR-256055 0.528 SLC15A1 protein P46059 UNIPROT muramyl dipeptide smallmolecule CHEBI:59414 ChEBI up-regulates activity binding 9606 BTO:0005156 15521010 t Tiberia HPepT1 transports muralyl dipeptide (MDP), activating NF-kB. SIGNOR-280445 0.8 PAK1 protein Q13153 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12151336 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). 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-91050 0.2 UBIAD1 protein Q9Y5Z9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000362 30518913 f miannu This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. SIGNOR-256205 0.7 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 0.562 F2RL1 protein P55085 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254859 0.2 RNF220 protein Q5VTB9 UNIPROT SIN3B protein O75182 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 20170641 t miannu Here we identify RNF220 (RING finger protein 220) as a novel ubiquitin ligase for Sin3B. RNF220 specifically interacts with Sin3B both in vitro and in vivo. Sin3B can be regulated by the ubiquitin-proteasome system. Co-expression of RNF220 promotes the ubiquitination and proteasomal degradation of Sin3B. SIGNOR-271943 0.429 PIM2 protein Q9P1W9 UNIPROT EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation 9606 19290049 t miannu Further, PIM2 triggered phosphorylation of AKT and 4EBP1 (XREF_FIG) clearly demonstrating the activation of PI3K pathway. SIGNOR-279091 0.414 aloxistatin chemical CHEBI:101381 ChEBI CTSL protein P07711 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 t miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260282 0.8 SRC protein P12931 UNIPROT NCKIPSD protein Q9NZQ3 UNIPROT up-regulates activity phosphorylation 9606 23342115 t miannu These results indicate that phosphorylation of SPIN90 by Src is essential for its synaptic targeting. SIGNOR-279387 0.414 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 0.588 PIM2 protein Q9P1W9 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273896 0.2 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248300 0.5 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr325 GQLRGSAtRALPPGP 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-250811 0.2 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 0.679 AMPK complex SIGNOR-C15 SIGNOR 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-252885 0.412 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 0.259 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190985 0.8 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 0.566 AHCYL1 protein O43865 UNIPROT PAPOLA protein P51003 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268329 0.246 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236745 0.914 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr527 PPKAKDPtVS 9606 35080342 t miannu AKT1 and AKT2 phosphorylate HSF1 at S326 but only AKT1 activates HSF1.|Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. SIGNOR-278371 0.405 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT down-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0000007 24841198 t lperfetto CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15|Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state. SIGNOR-265747 0.395 WWP1 protein Q9H0M0 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates ubiquitination 9606 15221015 t gcesareni Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7 SIGNOR-126581 0.533 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 0.332 ITGB1BP1 protein O14713 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-257638 0.732 ZM447439 chemical CHEBI:91376 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207923 0.8 MIB1 protein Q86YT6 UNIPROT PCM1 protein Q15154 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.  SIGNOR-272878 0.371 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 0.2 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 0.2 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 0.34 PARD6A protein Q9NPB6 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR form complex binding 9606 BTO:0004183 15761148 t lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. SIGNOR-227559 0.638 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM2 protein Q14416 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264071 0.8 STAT3 protein P40763 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11278729 t lperfetto Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells SIGNOR-251742 0.622 AGPAT5 protein Q9NUQ2 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-267012 0.8 PTPRH protein Q9HD43 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 28065597 t miannu We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. SIGNOR-277090 0.288 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 0.689 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268077 0.8 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity SIGNOR-232142 0.757 HOXA11 protein P31270 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001549 17688409 f miannu Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. SIGNOR-254469 0.294 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 0.8 CEP43 protein O95684 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR form complex binding 9606 16314388 t miannu Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring. SIGNOR-142358 0.2 MAP2K6 protein P52564 UNIPROT PAK6 protein Q9NQU5 UNIPROT up-regulates phosphorylation Tyr566 KSLVGTPyWMAPEVI 9606 15550393 t llicata Moreover, pak6 was directly activated by mkk6, and mutation of tyrosine 566 in a consensus mkk6 site (threonine-proline-tyrosine, tpy) in the activation loop of the pak6 kinase domain prevented activation by mkk6. SIGNOR-130975 0.2 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates activity phosphorylation Ser529 SNSGRARsDPTHQHR 9606 BTO:0001938 17229891 t llicata In the present study, we show that DYRK1A autophosphorylates, via an intramolecular mechanism, on Ser-520, in the PEST domain of the protein. | Instead, we demonstrate that this phosphorylation allows the binding of 14-3-3beta, which in turn stimulates the catalytic activity of DYRK1A. SIGNOR-251090 0.2 ARHGEF12 protein Q9NZN5 UNIPROT RHOA protein P61586 UNIPROT up-regulates guanine nucleotide exchange factor 9606 BTO:0001271 11094164 t gcesareni Here, we show that larg can activate rho in vivo SIGNOR-84657 0.905 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser380 PEQIKEDsLSEESAD -1 21880710 t miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. SIGNOR-262938 0.429 ERK1/2 proteinfamily SIGNOR-PF1 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-270160 0.2 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase SIGNOR-250314 0.492 (2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine chemical CID:11314340 PUBCHEM AKT1 protein P31749 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-258064 0.8 MAPK14 protein Q16539 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser113 STSVTPHsPSSPVGS 9606 BTO:0000007 16713578 t miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles SIGNOR-262948 0.316 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21697284 t gcesareni Exel-2880 (xl880, gsk1363089) is a small-molecule kinase inhibitor that targets members of the hgf and vegf receptor tyrosine kinase families, with additional inhibitory activity toward kit, flt-3, platelet-derived growth factor receptor _, and tie-2. SIGNOR-174552 0.8 CALM3 protein P0DP25 UNIPROT PPP3CA protein Q08209 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-266343 0.626 CDS1 protein Q92903 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates chemical modification 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267017 0.8 TRIM27 protein P14373 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33385414 t miannu Mechanically, TRIM27 ubiquitinates and degrades PPARgamma, following induces cleaved Caspase-3 and IL-1beta expression. SIGNOR-278734 0.289 SGK1 protein O00141 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 25790864 t gcesareni SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family SIGNOR-251673 0.2 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 0.7 CDK1 protein P06493 UNIPROT STMN1 protein P16949 UNIPROT up-regulates activity phosphorylation Ser25 QAFELILsPRSKESV 9606 8125092 t lperfetto SIGNOR-279803 0.641 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates activity binding 9606 29958106 t miannu The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. SIGNOR-255743 0.2 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 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-89268 0.394 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 0.334 CSNK1G2 protein P78368 UNIPROT CERT1 protein Q9Y5P4 UNIPROT down-regulates phosphorylation Ser132 SSLRRHGsMVSLVSG 9606 BTO:0000567 BTO:0000975 19005213 t lperfetto These results indicate that ckigamma2 hyperphosphorylates the serine-repeat motif of cert, thereby inactivating cert and down-regulating the synthesis of sphingomyelin. SIGNOR-182160 0.2 PTPN11 protein Q06124 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 11085989 t miannu SHP-2 is thus a positive regulator of ERK by leptin receptors, and both the adaptor function and the phosphatase activity of SHP-2 are critical for this regulation. Based on these data, we conclude that tyrosinephosphorylation of SHP-2 is a mediator of ERK activation viaTyr-985. This is likely to occur via Grb-2 binding to SHP-2 atthe C terminus followed by activation of the Ras-Raf pathwayas suggested for other signaling systems (55, 56) and morerecently for the leptin receptor (33). SIGNOR-263498 0.737 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL 9606 23650397 t gcesareni SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation SIGNOR-251670 0.46 ESR1 protein P03372 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000150 16169518 t gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. SIGNOR-140470 0.628 RASGEF1A protein Q8N9B8 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-183829 0.385 ACOT4 protein Q8N9L9 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271806 0.8 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001482 15705665 t We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs). SIGNOR-255950 0.395 ADIPOQ protein Q15848 UNIPROT ADIPOR1 protein Q96A54 UNIPROT up-regulates binding 9606 16622416 t milica Two adiponectin receptors, adipor1 and adipor2, have recently been identified. SIGNOR-146170 0.677 COP1 protein Q8NHY2 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 19805145 t miannu MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism SIGNOR-271893 0.2 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 0.808 Tifluadom chemical CHEBI:9591 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-258665 0.8 KDM5D protein Q9BY66 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264308 0.2 PRKCB protein P05771 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr705 WKLQRAItILDTEKS 9606 BTO:0000007 24920628 t miannu PKCβII causes the downregulation of TRPV1 by phosphorylating the channel. The increased threonine phosphorylation was substantially reduced by mutating Thr705, showing that Thr705 is indeed a major PKCβII phosphorylation site. SIGNOR-276638 0.2 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275770 0.398 tolazoline chemical CHEBI:28502 ChEBI ADRA2A protein P08913 UNIPROT down-regulates activity chemical inhibition 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258912 0.8 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 0.298 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194640 0.8 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 BTO:0000007 11259409 t miannu JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein. SIGNOR-250083 0.339 CRADD protein P78560 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-262642 0.923 EAF1 protein Q96JC9 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 t miannu Positive regulation of ell elongation activity depends on stable binding of eaf1 to the ell n terminus SIGNOR-138516 0.847 PIM1 protein P11309 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 20663873 t miannu Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1. SIGNOR-259820 0.317 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 0.764 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity 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-267803 0.421 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19389850 f Regulation miannu We analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. SIGNOR-251927 0.292 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266609 0.8 testolactone chemical CHEBI:9460 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.We report here that 1,4-androstadiene 3,17-dione (Ki 0.32 microM; kinact 0.91 X 10(-3)/sec) and testolactone (Ki 35 microM; kinact 0.36 X 10(-3)/sec) also cause a similar loss of aromatase activity. SIGNOR-258406 0.8 TWIST2 protein Q8WVJ9 UNIPROT SRPX protein P78539 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255497 0.208 A5/b1 integrin complex SIGNOR-C163 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257705 0.611 pralidoxime chemical CHEBI:8354 ChEBI ACHE protein P22303 UNIPROT up-regulates activity chemical activation -1 21215642 t Luana These compounds were synthesized, evaluated in vitro on human AChE (hAChE) inhibited by tabun, paraoxon, methylparaoxon and DFP and then compared to commercial hAChE reactivators (pralidoxime, HI-6, trimedoxime, obidoxime, methoxime) or previously prepared compounds (K027, K203). Three of these novel compounds showed a promising ability to reactivate hAChE comparable or better than the used standards.  SIGNOR-257889 0.8 SLC2A2 protein P11168 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 25421524 t The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. SIGNOR-267386 0.8 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 0.7 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 0.8 metformin chemical CHEBI:6801 ChEBI PCK1 protein P35558 UNIPROT down-regulates quantity 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-158062 0.8 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 10913145 t gcesareni We find that, in vitro, pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. SIGNOR-79955 0.374 (S)-selisistat chemical CHEBI:90371 ChEBI SIRT1 protein Q96EB6 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191511 0.8 GATA2 protein P23769 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8195185 f irozzo Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3. SIGNOR-256052 0.43 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15109499 t Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers SIGNOR-252929 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248371 0.614 NFIA protein Q12857 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268896 0.2 NEDD4 protein P46934 UNIPROT NANOS2 protein P60321 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28585553 t miannu We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.|To examine whether complex formation of NEDD4 and NDFIP2 promotes NANOS2 ubiquitination in vivo, FLAG tagged NANOS2 was expressed in HEK293 cells with or without MYC-NEDD4 and MYC-NDFIP2. SIGNOR-278770 0.2 AKT1 protein P31749 UNIPROT NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t llicata Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype. SIGNOR-198913 0.424 F2RL1 protein P55085 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254843 0.2 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr129 ITEIADLtQKIFDLR 9606 BTO:0000671 18986304 t llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). SIGNOR-182049 0.2 WNT5A protein P41221 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60379 0.32 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7889942 t inferred from 70% family members gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-270075 0.2 ENAH protein Q8N8S7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268392 0.7 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 0.642 PRKCD protein Q05655 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 23814099 t miannu We next demonstrated by immunoprecipitation that IL-32\u03b2 interacted with PKC\u03b4 and C/EBP\u03b1, thereby mediating C/EBP\u03b1 Ser-21 phosphorylation by PKC\u03b4. SIGNOR-279427 0.2 BHLHE40 protein O14503 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14672706 f lperfetto Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression SIGNOR-253716 0.533 SPDYA protein Q5MJ70 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 33015044 t lperfetto Speedy/RINGO A, a noncanonical activator of CDK2, was recently identified as a key regulator for CDK2 recruitment to meiotic telomeres SIGNOR-263310 0.791 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 0.4 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256324 0.283 NSF protein P46459 UNIPROT SNAP25 protein P60880 UNIPROT down-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 16679567 t miannu NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers SIGNOR-263974 0.722 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 0.7 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 0.2 PRKAA1 protein Q13131 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276839 0.2 CNKSR1 protein Q969H4 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15845549 t gcesareni Here we demonstrate that the connector enhancer of ksr1, cnk1, mediates src-dependent tyrosine phosphorylation and activation of raf-1. Cnk1 binds preactivated raf-1 and activated src and forms a trimeric complex. SIGNOR-135674 0.71 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-267285 0.7 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 0.558 N-[4-[(4-Ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(E)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)ethenyl]-4-methylbenzamide chemical CID:53302361 PUBCHEM BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 32069833 t lperfetto HG6-64-1 is a specific BRAF inhibitor SIGNOR-261986 0.8 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 0.638 GSK3B protein P49841 UNIPROT SOX10 protein P56693 UNIPROT down-regulates quantity phosphorylation 9606 26461473 t miannu Besides, GSK3\u03b2 phosphorylates SOX10 at CPD domain and facilitates Fbxw7\u03b1-mediated SOX10 degradation.|Besides, GSK3beta phosphorylates SOX10 at CPD domain and facilitates Fbxw7alpha mediated SOX10 degradation. SIGNOR-279617 0.406 AMPK complex SIGNOR-C15 SIGNOR MAPK14 protein Q16539 UNIPROT up-regulates activity 10090 20660302 f P38 MAPK mediates the effect of AMPK on Gr induced transcriptional activity SIGNOR-255951 0.28 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 0.728 FOXO3 protein O43524 UNIPROT STK11 protein Q15831 UNIPROT down-regulates quantity transcriptional regulation 22848740 t SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor SIGNOR-255758 0.634 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAQ protein P50148 UNIPROT up-regulates binding 9606 20331961 t inferred from 70% family members gcesareni The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits) SIGNOR-269966 0.2 AKT1 protein P31749 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates activity phosphorylation Ser72 PPRKRLKsKGSDKDF 9606 19270695 t miannu We further show that Akt1 phosphorylates Skp2 at Ser72, which is required to disrupt the interaction between Cdh1 and Skp2. SIGNOR-278274 0.515 WNT4 protein P56705 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60370 0.293 LYN protein P07948 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276369 0.357 SMO protein Q99835 UNIPROT KIF7 protein Q2M1P5 UNIPROT up-regulates activity relocalization 10090 19666503 t lperfetto Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins. SIGNOR-209605 0.632 SRC protein P12931 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000876 25624455 t miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. SIGNOR-254740 0.449 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1742 KAQAKVGsLDNAHHV 9606 BTO:0000567 11029056 t miannu CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA SIGNOR-250003 0.36 SP1 protein P08047 UNIPROT CD34 protein P28906 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 10989198 t lperfetto Activation of the CD34 promoter by Sp1 requires the presence of a binding domain at -48 bp as well as the 5' untranslated region, which also binds Sp1 SIGNOR-241481 0.263 SUCLG2 protein Q96I99 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-266264 0.93 CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 t fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. SIGNOR-192697 0.765 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser44 GKSSVLEsLVGRDLL 9606 25192600 t miannu The schematic for GSK3beta phosphorylating Drp1 at Ser 40 and Ser 44 was shown. SIGNOR-278479 0.388 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 11602604 t lperfetto Rgs16 contains two conserved tyrosine residues in the rgs box, tyr(168) and tyr(177), which are predicted sites of phosphorylation. Rgs16 underwent phosphorylation in response to m2 muscarinic receptor or egfr stimulation in hek 293t or cos-7 cells, which required egfr kinase activity. Mutational analysis suggested that rgs16 was phosphorylated on both tyrosine residues (tyr(168) tyr(177)) after egf stimulation.Phosphorylated rgs16 demonstrated enhanced gtpase accelerating (gap) activity on galpha(i). Mutation of tyr(168) to phenylalanine resulted in a 30% diminution in rgs16 gap activity mutation of tyr(177) to phenylalanine had no effect on rgs16 gap activity but also abolished its regulation of g(i)-mediated signal transduction in these cells. SIGNOR-111024 0.415 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr791 TPMYGSQtPLQDGSR 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143931 0.776 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 0.515 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1A protein P08908 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-257516 0.8 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 20577053 t gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-166365 0.489 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 21154127 t irozzo Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. SIGNOR-255819 0.8 cholesterol smallmolecule CHEBI:16113 ChEBI pregnenolone smallmolecule CHEBI:16581 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268629 0.8 TLR2 protein O60603 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266740 0.673 cabozantinib chemical CHEBI:72317 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207845 0.8 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 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-251982 0.642 CSNK1A1 protein P48729 UNIPROT FOXO1 protein Q12778 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-183658 0.418 ER stress stimulus SIGNOR-ST9 SIGNOR BBC3 protein Q9BXH1 UNIPROT up-regulates 9606 22492984 f miannu Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196938 0.7 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 0.2 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205936 0.8 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 0.437 ITGB1BP1 protein O14713 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257648 0.732 TRIM27 protein P14373 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates activity ubiquitination Lys73 RRSQHARkETEFLRL 10090 35670107 t K6 corresponds to the 6th Lysine, which is in position 73 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-270346 0.2 HTR4 protein Q13639 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-257154 0.25 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser560 SIGNOR-277814 0.2 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 0.582 NMBR protein P28336 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256775 0.25 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 0.278 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR BIRC6 protein Q9NR09 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271318 0.38 FZD1 protein Q9UP38 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253512 0.688 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 0.754 NR1I2 protein O75469 UNIPROT CYP3A4 protein P08684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000003 18540626 f miannu Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals. SIGNOR-254835 0.519 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-256472 0.741 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2A protein P49459 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271361 0.674 ACP3 protein P15309 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity chemical modification -1 18940592 t Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. SIGNOR-269739 0.8 CHEK2 protein O96017 UNIPROT CDK11B protein P21127 UNIPROT up-regulates activity phosphorylation 9606 23178491 t miannu CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11p110|Unexpectedly, CHK2 kinase constitutively phosphorylated CDK11(p110) in a DNA damage-independent manner. SIGNOR-279458 0.2 CAMTA1 protein Q9Y6Y1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-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-259100 0.7 ixazomib chemical CHEBI:90942 ChEBI PSMB5 protein P28074 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194509 0.8 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206139 0.8 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 0.8 TCAP protein O15273 UNIPROT TTN protein Q8WZ42 UNIPROT up-regulates activity binding 9606 BTO:0001103 32937135 t lperfetto TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc SIGNOR-264854 0.908 CDK2 protein P24941 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates activity phosphorylation Ser251 EVSIRVGsPQPSSSG 9606 BTO:0002181 29229926 t miannu  During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. SIGNOR-277374 0.329 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246281 0.2 AKT1 protein P31749 UNIPROT GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 t llicata We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter. SIGNOR-139782 0.514 BUB1 protein O43683 UNIPROT BUB1 protein O43683 UNIPROT up-regulates activity phosphorylation Ser969 FTAKCETsGFQCVEM -1 26658523 t miannu  Conversely, Bub1 is an active kinase regulated by intra-molecular phosphorylation at the P+1 loop. SIGNOR-277186 0.2 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 BTO:0000801;BTO:0000776 10347215 t miannu Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. SIGNOR-68010 0.809 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Thr310 GTARRTGtPSDPRRR -1 12885254 t GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro SIGNOR-251235 0.388 PINK1 protein Q9BXM7 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates phosphorylation Ser65 DYNIQKEsTLHLVLR 24784582 t Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. SIGNOR-270341 0.604 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 0.525 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 0.732 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 0.832 HBB protein P68871 UNIPROT CD163 protein Q86VB7 UNIPROT up-regulates activity binding 9606 16522161 t Regulation miannu These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells. SIGNOR-251746 0.442 AT9283 chemical CID:11696609 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190017 0.8 C9 protein P02748 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263441 0.49 VPS11 protein Q9H270 UNIPROT RDX protein P35241 UNIPROT up-regulates activity binding 9606 BTO:0000567 21148287 t Sara Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. SIGNOR-261312 0.347 NPFFR1 protein Q9GZQ6 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256851 0.25 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256191 0.8 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 0.4 CHKA protein P35790 UNIPROT PLIN2 protein Q99541 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr232 TKLHSRAyQQALSRV 9606 BTO:0000527 34929314 t lperfetto In addition, as a protein kinase, CHKalpha2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth  SIGNOR-267649 0.2 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-219269 0.781 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195543 0.8 HIPK2 protein Q9H2X6 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation 9606 16212962 t miannu HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations.|This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro. SIGNOR-279465 0.537 AKT proteinfamily SIGNOR-PF24 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 t gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. SIGNOR-252345 0.2 IFNAR complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260436 0.2 UVB radiation stimulus SIGNOR-ST17 SIGNOR PAH protein P00439 UNIPROT up-regulates 9606 9204951 f miannu UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. SIGNOR-252207 0.7 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys682 SAVSHQGkRNPKSPL 9606 21791603 t miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). SIGNOR-272730 0.581 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr2229 QAEEREHtLRRCQQE 9606 22820163 t lperfetto Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1 SIGNOR-198353 0.335 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 0.2 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 0.2 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 8816480 t gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 SIGNOR-43947 0.636 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Thr991 SAYTYERtLMMEQRS 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-260912 0.444 Volasertib chemical CID:10461508 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190290 0.8 GPHN protein Q9NQX3 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 t miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264974 0.473 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 0.7 RAD52 protein P43351 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27649245 f lperfetto Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals. SIGNOR-251507 0.7 ROCK2 protein O75116 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation 9606 25412762 t miannu In addition, an in vitro kinase assay with mixed recombinant GST-ROCK2 and MLC2 revealed that ROCK2 phosphorylated WT MLC2, but not MLC2 S15A mutant, indicating that it phosphorylates MLC2 at S15 in vitro (XREF_FIG). SIGNOR-279103 0.598 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 0.298 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 0.327 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 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-184789 0.86 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 0.8 CTNNB1 protein P35222 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165 19000719 t Through Armadillo repeat domain gcesareni Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential. SIGNOR-236858 0.775 SPRY2 protein O43597 UNIPROT CBLB protein Q13191 UNIPROT down-regulates binding 9606 11053437 t gcesareni One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis. SIGNOR-83507 0.486 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 0.2 RASGEF1B protein Q0VAM2 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183835 0.297 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 0.346 BGJ-398 chemical CHEBI:63451 ChEBI FGFR2 protein P21802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190266 0.8 PIM1 protein P11309 UNIPROT 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-128260 0.418 MYC protein P01106 UNIPROT HLA-C protein P10321 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254602 0.256 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 0.464 Fluocinonide chemical CHEBI:5109 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 t gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. SIGNOR-248218 0.8 CDK5 protein Q00535 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates activity phosphorylation Ser408 SIKSEPIsPPRDRMT 9606 BTO:0004102 12691662 t lperfetto Cdk5-mediated inhibition of the protective effects of transcription factor mef2 in neurotoxicity-induced apoptosis.We have identified the prosurvival transcription factor mef2 as a direct nuclear target of cdk5. Cdk5 phosphorylates mef2 at a distinct serine in its transactivation domain to inhibit mef2 activity. SIGNOR-100574 0.506 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. SIGNOR-249260 0.2 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 0.2 CEBPB protein P17676 UNIPROT GFER protein P55789 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 20690902 f miannu In the present study, we investigated transcription of hHSS triggered by EGF (epidermal growth factor) and the role of C/EBPβ (CCAAT/enhancer-binding protein β) as a potential core factor responsible for hHSS transcription in HepG2 cells. The results show that EGF suppresses hHSS mRNA expression at early time points. Using a promoter deletion assay, we identified a proximal region (-358/-212) that is required for EGF suppression. Overexpression of C/EBPβ enhances EGF suppression of hHSS, and mutation of the C/EBPβ-binding site at -292/-279 or siRNA (short interfering RNA) interference abolishes EGF suppression. SIGNOR-253772 0.2 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 0.8 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM6A protein O15550 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-273462 0.8 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 0.552 CSF2RA protein P15509 UNIPROT JAK2 protein O60674 UNIPROT up-regulates 9606 9028317 f gcesareni We show that the amount of jak2 physically associated with gm-csfr beta chain is increased after gm-csf stimulation and that gm-csf triggers both beta chain and jak2 tyrosine phosphorylation SIGNOR-46334 0.533 NANOG protein Q9H9S0 UNIPROT FOXA2 protein Q9Y261 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-253166 0.452 PPM1D protein O15297 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates dephosphorylation Thr183 RQADSEMtGYVVTRW 9606 15870257 t gcesareni Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180. SIGNOR-135976 0.297 doramapimod chemical CHEBI:40953 ChEBI TNF protein P01375 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190335 0.8 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 0.518 EN1 protein Q05925 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265776 0.452 LTBR protein P36941 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 12571250 t lperfetto Endogenous association of traf2, traf3, ciap1, and smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. SIGNOR-97950 0.586 MTA1 protein Q13330 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000812 18719363 f miannu Screening for the expression of angiogenic cytokines expressed by ovarian cancer cells revealed MTA1-mediated upregulation of the oncogenic and angiogenic cytokine GRO (growth-regulated oncogene, CXCL1). SIGNOR-254598 0.2 RPS6KA5 protein O75582 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates phosphorylation 9606 15010469 t gcesareni We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1. SIGNOR-265314 0.2 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268996 0.25 Neuregulin proteinfamily SIGNOR-PF37 SIGNOR ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates activity binding 9606 18415007 t miannu The neuregulin family consists of four genes, NRG1-4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases SIGNOR-256161 0.908 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 19175684 f gcesareni In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs. SIGNOR-183532 0.441 YY1 protein P25490 UNIPROT FCER1A protein P12319 UNIPROT up-regulates quantity by expression 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. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells SIGNOR-254290 0.2 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192880 0.8 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 7503989 t gcesareni Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm. SIGNOR-26677 0.8 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr384 LCEDLPGtEDFVGHQ -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251199 0.694 SDC4 protein P31431 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1. SIGNOR-199632 0.356 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203580 0.777 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0002181 30684133 t miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. SIGNOR-277427 0.2 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 0.935 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269489 0.8 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNI2 protein P48788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136786 0.344 PTPN9 protein P43378 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation 9606 20335174 t miannu Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. SIGNOR-277170 0.304 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t lperfetto Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. SIGNOR-244634 0.2 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 0.8 PHLPP2 protein Q6ZVD8 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 t PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. SIGNOR-248730 0.2 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 0.605 trichostatin A chemical CHEBI:46024 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-258011 0.8 AXL protein P30530 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr376 DRVKSTAyLSPQELE 9606 BTO:0000007 31230815 t done miannu TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6). SIGNOR-274119 0.2 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT up-regulates activity phosphorylation Tyr345 PERNEGVyTAIAVQE 9534 BTO:0004055 11163214 t PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs. SIGNOR-251431 0.597 PRKACA protein P17612 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity phosphorylation Ser50 HVHAVREsQVELREQ 11283605 t miannu PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation SIGNOR-250053 0.307 AXIN1 protein O15169 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Other proteins, such as the serine/threonine kinase fused (fu), can function in concert with the e3 ligase smurf to regulate ubiquitination and proteolysis of the bmp receptor SIGNOR-195552 0.331 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 0.697 MKRN1 protein Q9UHC7 UNIPROT TERT protein O14746 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 15805468 t miannu MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length.  SIGNOR-271529 0.475 ACVR2A protein P27037 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 9748228 t fspada The major bmp7 type i receptor observed was alk2, SIGNOR-60234 0.664 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 0.7 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 0.7 CBLC protein Q9ULV8 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 12226085 t miannu In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.  SIGNOR-272605 0.761 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 0.7 PLCG2 protein P16885 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268454 0.8 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser295 FPFRNLGsPTQVISK 9606 23977114 t lperfetto Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined SIGNOR-202532 0.343 LLGL1 protein Q15334 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-270903 0.541 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 19088846 t gcesareni For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated. SIGNOR-182817 0.854 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser649 PVLYMQPsPL 9606 12620228 t llicata Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth. SIGNOR-98984 0.2 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 0.29 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT down-regulates activity relocalization 443947 BTO:0000964 22407360 t miannu Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane. SIGNOR-265781 0.2 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 0.589 RIPK3 protein Q9Y572 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates activity phosphorylation Ser473 SGVKRSRsGEGEVSG 9606 34419074 t miannu These results indicate that TRIM28 phosphorylation at S473 is RIPK3-dependent and suggest that RIPK1/RIPK3 activation induces TRIM28 phosphorylation at S473, which may play an important role in the regulation of transcriptional activity. SIGNOR-279107 0.2 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258030 0.8 IGF1 protein P05019 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f inferred from 70% of family members 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-269890 0.275 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 0.659 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 17386266 t lperfetto Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity. SIGNOR-236705 0.585 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227870 0.895 NVP-AEW541 chemical CID:11476171 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194892 0.8 AMPK complex SIGNOR-C15 SIGNOR ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser761 QSIPRSAsYPCAAPR 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-266365 0.249 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser163 KRFSFKKsFKLSGFS -1 1560845 t gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin SIGNOR-249650 0.73 DUX4 protein Q9UBX2 UNIPROT HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24278031 f miannu HEY1, a repressor of myogenesis, is activated by DUX4 through a MaLR promoter. SIGNOR-253840 0.274 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates relocalization 9606 19289081 t gcesareni Ranbp3 directly recognizes dephosphorylated smad2/3, which results from the activity of nuclear smad phosphatases, and mediates nuclear export of smad2/3 in a ran-dependent manner SIGNOR-184608 0.389 YBX1 protein P67809 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255612 0.247 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 0.724 IRF4 protein Q15306 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity 9606 BTO:0000801 22378047 t lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249560 0.456 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 PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192604 0.8 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 0.487 SYN2 protein Q92777 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-269182 0.2 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 0.892 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 0.628 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 0.292 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -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-178387 0.741 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser99 AGEKEAKsD 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-76278 0.2 S100A9 protein P06702 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 t miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner SIGNOR-261936 0.2 TPO protein P07202 UNIPROT TG protein P01266 UNIPROT up-regulates activity catalytic activity 9606 23349248 t miannu After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-259914 0.505 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252084 0.2 PKN1 protein Q16512 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun SIGNOR-152765 0.378 KMT2A protein Q03164 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 22303254 f Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones SIGNOR-268626 0.7 TBCK protein Q8TEA7 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 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-266701 0.7 MAP3K7 protein O43318 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization 9606 BTO:0000567 9480845 f lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene. SIGNOR-55716 0.671 ALK protein Q9UM73 UNIPROT ATIC protein P31939 UNIPROT up-regulates activity phosphorylation Tyr104 RVVACNLyPFVKTVA 9606 BTO:0002181 18845790 t miannu ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity. ATIC activity is enhanced in the presence of NPM-ALK in vitro.The ATIC activity is enhanced by NPM-ALK in HEK-293T-Rex cells. SIGNOR-276171 0.377 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 20395206 t gcesareni With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation. SIGNOR-164800 0.887 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation SIGNOR-275804 0.2 NEK2 protein P51955 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization phosphorylation Thr210 TNEIFYCtFRRLDPE 10090 BTO:0000584 34315872 t miannu NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen.  SIGNOR-277314 0.2 MDM2 protein Q00987 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates quantity by destabilization ubiquitination Lys74 YHSDDYIkFLRSIRP 9606 26832969 t miannu MDM2 induces ubiquitination of HDAC1 in VSMCs.|Under calcification inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. SIGNOR-278761 0.468 GSK3B protein P49841 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates phosphorylation Ser303 QATYFPPsPPSSEPG 9606 24398687 t lperfetto Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5 SIGNOR-203627 0.368 ULK2 protein Q8IYT8 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. SIGNOR-173095 0.2 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser257 SWLGARSsRPASPCN -1 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276767 0.643 CCNK protein O75909 UNIPROT CyclinK/CDK12 complex SIGNOR-C37 SIGNOR form complex binding 9606 22012619 t miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells SIGNOR-176783 0.942 RUVBL2 protein Q9Y230 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270940 0.509 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-236848 0.759 MAPK14 protein Q16539 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity SIGNOR-48349 0.415 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-145122 0.477 TRAC protein P01848 UNIPROT TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ SIGNOR-255297 0.2 AURKA protein O14965 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 t miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. SIGNOR-276061 0.332 GATA4 protein P43694 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001086 32376282 f 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-265480 0.7 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. 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-249366 0.922 PTPN1 protein P18031 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity dephosphorylation 9606 22169477 t miannu Finally, we demonstrated that wild-type PTP1B directly dephosphorylated myc-tagged PERK that had been isolated from tunicamycin-treated HEK293T cells by immunoprecipitation ( xref ).|The ability of PTP1B to dephosphorylate Tyr619 and inactivate PERK is fine tuned by the production of H 2 S by CSE in response to ER stress. SIGNOR-277051 0.267 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 0.48 PAK1 protein Q13153 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0001033 29572236 f miannu  RAC1 activation induces the actin remodeling and membrane ruffling necessary to form macropinosomes by activating PAK kinases SIGNOR-277768 0.7 FOXO3 protein O43524 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-217881 0.7 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 0.266 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263420 0.537 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199183 0.385 MDM2 protein Q00987 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates ubiquitination 9606 23252402 t gcesareni Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1. SIGNOR-200197 0.476 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 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-101119 0.926 PRKACA protein P17612 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t miannu Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII). Incubation of Rad with PKA decreases GTP binding by 60-70%, but this effect seems to be independent of phosphorylation, as it is observed with the Ser273-->Ala mutant of Rad containing a mutation at the site of PKA phosphorylation. SIGNOR-250048 0.34 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB1 protein Q9Y5G3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265681 0.2 VEGFA protein P15692 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157100 0.82 SRC protein P12931 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates activity phosphorylation Tyr324 DNLESQTyEVFEKDP 9606 BTO:0002181 32759981 t miannu Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity. SIGNOR-277523 0.261 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 0.7 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 0.378 DLX3 protein O60479 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17060321 f gcesareni Here we show that bmp2 induces dlx3, a homeodomain protein that activates runx2 gene transcription. Small interfering rna knockdown studies in osteoblasts validate that dlx3 is a potent regulator of runx2. SIGNOR-150177 0.397 SDC4 protein P31431 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1. SIGNOR-199638 0.247 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1179 GLENGLNyIDLDLVK 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-157730 0.868 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation 9606 34144039 t miannu PDGFR\u03b2 binds and phosphorylates Abl2 in cells.|We report here the molecular mechanisms by which PDGFR\u03b2 binds, phosphorylates, and activates the Abl2 kinase. SIGNOR-279640 0.303 N-[3-[[5-bromo-4-[2-(1H-imidazol-5-yl)ethylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91357 ChEBI PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190804 0.8 PEBP1 protein P30086 UNIPROT RAF1 protein P04049 UNIPROT down-regulates binding 9606 10490027 t gcesareni Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras. SIGNOR-70838 0.762 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 0.2 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT up-regulates activity phosphorylation Ser135 VNNESGEsQRGTDFS -1 18571408 t miannu Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). SIGNOR-262636 0.381 6-[2-tert-butyl-5-(6-methyl-2-pyridinyl)-1H-imidazol-4-yl]quinoxaline chemical CHEBI:91391 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206715 0.8 Crenolanib chemical CID:10366136 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191124 0.8 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 0.334 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.781 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 0.526 LRFN5 protein Q96NI6 UNIPROT PTPRD protein P23468 UNIPROT up-regulates activity binding 9606 BTO:0000938 27225731 t miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). SIGNOR-264086 0.277 PTPN5 protein P54829 UNIPROT GRIA2 protein P42262 UNIPROT down-regulates activity dephosphorylation 9606 21883219 t miannu One study showed that stimulation of the metabotrophic glutamate receptor mGluR5 leads to a STEP mediated tyrosine dephosphorylation of GluA2 and internalization of GluA1 and GluA2, although the tyrosine residue on GluA2 that is dephosphorylated by STEP remains unidentified. SIGNOR-277040 0.412 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK5 protein Q16478 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-264474 0.8 CTDP1 protein Q9Y5B0 UNIPROT WEE1 protein P30291 UNIPROT up-regulates activity dephosphorylation 9606 27670139 t miannu At mitosis exit, Fcp1 promoted inhibitory Cdk1 phosphorylation by dephosphorylating Wee1, and ubiquitin dependent cyclin B degradation by dephosphorylating Cdc20 and USP44.|This lead us to hypothesize that, during prolonged mitosis in AMCDs treated cancer cells, progressive Fcp1 induced Wee1 reactivation might lead to progressive loss of Cdk1 activity that weakens the SAC to a point in which the mitotic state could not be sustained . SIGNOR-277142 0.382 PPM1G protein O15355 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation 9606 22361354 t miannu After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. |ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G. SIGNOR-277158 0.303 MAPK1 protein P28482 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277857 0.2 ritanserin chemical CHEBI:64195 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258691 0.8 SYK protein P43405 UNIPROT LCK protein P06239 UNIPROT down-regulates activity phosphorylation Tyr192 NLDNGGFyISPRITF 9606 BTO:0000782 8798764 t lperfetto Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling SIGNOR-246562 0.592 PPM1F protein P49593 UNIPROT CAMK1 protein Q14012 UNIPROT down-regulates activity dephosphorylation 9606 11726284 t miannu Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV. SIGNOR-277111 0.461 EPHB2 protein P29323 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 9632142 t lperfetto We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation SIGNOR-58142 0.566 AL/b2 integrin complex SIGNOR-C169 SIGNOR ICAM1 protein P05362 UNIPROT up-regulates activity binding 10090 BTO:0003104 12808052 t lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. SIGNOR-253364 0.835 BKM120 chemical CHEBI:71954 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252656 0.8 cabozantinib chemical CHEBI:72317 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207842 0.8 ABTB1 protein Q969K4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 f miannu Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. SIGNOR-260046 0.7 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191012 0.8 PTPN2 protein P17706 UNIPROT STAT6 protein P42226 UNIPROT down-regulates activity dephosphorylation 9606 17210636 t gcesareni These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors SIGNOR-235192 0.679 PP121 chemical CHEBI:50915 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206304 0.8 NEDD4L protein Q96PU5 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity ubiquitination 9606 33608556 t miannu Nedd4l promotes TRAF3 to interact with cIAP1/2 and HECTD3.|Ubiquitination of TRAF3 by Nedd4l promotes interaction of TRAF3 with proteins such as cIAP1/2, HECTD3, and TBK1. SIGNOR-278587 0.27 NCOA1 protein Q15788 UNIPROT RARA protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255932 0.71 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182967 0.743 PLK1 protein P53350 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr466 REAWRIFtPLLHQIE 9606 BTO:0000007 29138396 t lperfetto We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD SIGNOR-267581 0.346 CDC42BPA protein Q5VT25 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates activity phosphorylation Thr560 MRQSRRStQGVTLTD BTO:0000298 11399775 t llicata Identification of the Phosphorylation Site of p85 on Threonine 560 by MRCKα-CAT | Wild-type p85 but not the mutant p85AA, when phosphorylated in vitro with MRCKα-CAT, showed significant reduction in the rate of MLC2 dephosphorylation. These results confirm a similar observation with MBS130 where phosphorylation of a conserved threonine 695 within a highly conserved motif was essential for the inhibition of phosphatase catalytic activity SIGNOR-250724 0.558 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 0.7 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 0.766 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 0.597 ZMYND8 protein Q9ULU4 UNIPROT ZMYND8 protein Q9ULU4 UNIPROT up-regulates activity binding 9606 BTO:0000007 27477906 t lperfetto We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D|Co-immunoprecipitation between ectopically expressed FLAG-tagged JARID1D and endogenous ZMYND8 protein. SIGNOR-262037 0.2 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25838379 f lperfetto The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. SIGNOR-262333 0.7 α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI up-regulates quantity precursor of 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-268138 0.8 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 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A10/b1 integrin complex SIGNOR-C167 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-259021 0.446 SMAD1/4 complex SIGNOR-C85 SIGNOR CEBPB protein P17676 UNIPROT up-regulates activity binding 9606 18854943 t 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-253552 0.561 MAPK1 protein P28482 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-120136 0.311 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 0.416 MAPK14 protein Q16539 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates transcriptional regulation 10116 11904165 f ggiuliani These data indicate that TGF-beta1-induced p38 activation is involved in TGF-beta1-stimulated collagen synthesis. SIGNOR-255958 0.7 SMURF1 protein Q9HCE7 UNIPROT FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28408404 t miannu Smurf1 mediates Kindlin-2 proteasomal degradation.|Smurf1 promotes polyubiquitination of Kindlin-2. SIGNOR-278614 0.2 PTGES3 protein Q15185 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding -1 9817749 t lperfetto The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23, which is thought to regulate the binding and release of substrate polypeptide from Hsp90.  SIGNOR-262831 0.916 POU2F1 protein P14859 UNIPROT HOXD10 protein P28358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25301728 f miannu Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11 SIGNOR-205540 0.2 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252657 0.8 ERK1/2 proteinfamily SIGNOR-PF1 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-270185 0.2 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252687 0.425 EEF1A1 protein P68104 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205606 0.297 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263009 0.2 ITCH protein Q96J02 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys420 GLGSELSkPGVLASQ 9606 BTO:0002181 19881509 t Giorgia These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation SIGNOR-260363 0.646 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 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-84967 0.765 CTNND2 protein Q9UQB3 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-252120 0.2 PCDH19 protein Q8TAB3 UNIPROT GABRA6 protein Q16445 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C334,SIGNOR-C328,SIGNOR-C329 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267221 0.2 ATR protein Q13535 UNIPROT MCM4 protein P33991 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6. SIGNOR-169412 0.724 nutlin-3A chemical CID:11433190 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194874 0.8 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 0.85 VASP protein P50552 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268393 0.7 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 0.727 LRRK2 protein Q5S007 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity phosphorylation Thr474 KFLQEALtMRQFDHP 9606 26365310 t miannu LRRK2 inhibits FAK activation in a kinase dependent manner, meaning that the G2019S gain-of-function mutation results in the excessive inhibition of FAK activation and microglial motility.|Taken together, these results suggest that LRRK2 directly phosphorylate FAK at T474. SIGNOR-278281 0.2 CHEK1 protein O14757 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Thr12 KQTARKStGGKAPRK 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-160557 0.2 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107676 0.34 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 0.8 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 0.327 SRC protein P12931 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity phosphorylation 9606 21712022 t miannu Src dependent phosphorylation of TLR4 is significantly increased in Cftr-KO cholangiocytes.|TLR4 can be activated through the phosphorylation of its TIR domains by Src, a non receptor tyrosine kinase 28. SIGNOR-279658 0.588 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 0.404 GMPS protein P49915 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267341 0.8 AKT1 protein P31749 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates quantity phosphorylation Ser257 PSRPPRPsRPPPPTP 9606 BTO:0000815 30517763 t miannu AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation SIGNOR-272922 0.319 F2R protein P25116 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254847 0.2 Y-27632 chemical CHEBI:75393 ChEBI ROCK1 protein Q13464 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207890 0.8 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT unknown phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 10068673 t llicata These results indicate that btk phosphorylates wasp on its tyrosine 291 SIGNOR-86004 0.743 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 0.2 ROS stimulus SIGNOR-ST2 SIGNOR ARNT protein P27540 UNIPROT up-regulates quantity by expression 22387692 f lperfetto Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species. SIGNOR-253689 0.7 DLG3 protein Q92796 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270897 0.534 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCND1 protein P24385 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189972 0.8 NEK6 protein Q9HC98 UNIPROT BSG protein P35613 UNIPROT down-regulates activity phosphorylation Ser368 GSAPLKSsGQHQNDK 9606 31016558 t done miannu These results indicate that NEK6 directly interacts with CD147 and phosphorylates the protein at serine-252 in Huh-7 cells. SIGNOR-273882 0.2 AGT protein P01019 UNIPROT TRPC6 protein Q9Y210 UNIPROT up-regulates activity 9606 24850910 f We demonstrated that Ang II evokes concentration-dependent activation of podocyte TRPC6 channels SIGNOR-253331 0.305 GPS1 protein Q13098 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270774 0.924 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRA protein P10827 UNIPROT up-regulates activity chemical activation 9606 6777394 t miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-258402 0.8 DUSP6 protein Q16828 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation 9606 20638106 t lperfetto Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase. SIGNOR-277006 0.904 superoxide smallmolecule CHEBI:18421 ChEBI SOD3 protein P08294 UNIPROT up-regulates activity precursor of 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272274 0.8 BKM120 chemical CHEBI:71954 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190389 0.8 MAP3K7 protein O43318 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 9480845 f lperfetto These results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway. SIGNOR-55713 0.597 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 0.252 SPRY4 protein Q9C004 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0002058 20501643 f miannu Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a non-transformed lung epithelial cell line with shRNA to Spry4 led to decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor. SIGNOR-253036 0.7 MDGA2 protein Q7Z553 UNIPROT DMAP1 protein Q9NPF5 UNIPROT up-regulates quantity by stabilization binding 9606 26206665 t miannu The anti-tumorigenic effect of MDGA2 was mediated through direct stabilising of DNA methyltransferase 1 associated protein 1 (DMAP1), which played a tumour suppressive role in gastric cancer. MDGA2 expression and MG132 treatment increased the level of DMAP1, suggesting that the MDGA2–DMAP1 interaction stabilises DMAP1 by inhibiting its ubiquitin-mediated degradation. SIGNOR-264240 0.348 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr340 RGQRDSSyYWEIEAS 10090 BTO:0001482 8876196 t  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. SIGNOR-251361 0.617 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser205 GVRRRRLsNVSLTGV 9606 10867018 t llicata Activation of the serine/threonine kinase, protein kinase d (pkd/pkc mu) via a phorbol ester/pkc-dependent pathway involves phosphorylation events. the second autophosphorylation site (ser(203)) lies in that region of the regulatory domain SIGNOR-78676 0.2 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 0.521 AGRP protein O00253 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-268714 0.55 AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 t scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. SIGNOR-267861 0.8 CCR6 protein P51684 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000584 37398643 f miannu Senescent tumor cells acquire SASP with enhanced secretion of CCL20, acting on CCR6 receptors of precursor macrophages to favor the immunocompromised M2 phenotype.  SIGNOR-278043 0.7 NAB2 protein Q15742 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 f miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. SIGNOR-253888 0.576 AKT proteinfamily SIGNOR-PF24 SIGNOR CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t lperfetto Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro SIGNOR-244172 0.2 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr1320 Y>1319 9606 BTO:0002181 24583284 t miannu CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation. SIGNOR-277877 0.636 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 0.2 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 0.738 DPM1 protein O60762 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 t lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. SIGNOR-262563 0.787 TNF protein P01375 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity 10090 10485710 f lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-70616 0.273 TREX complex complex SIGNOR-C444 SIGNOR mRNA_nuclear_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 0.7 FGG protein P02679 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-263393 0.763 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 0.8 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser246 DSVSDQFsVEFEVES 9606 20708156 t gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination SIGNOR-167509 0.345 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 17010989 t lperfetto Pkc-betaii sensitizes cardiac myofilaments to ca2+ by phosphorylating troponin i on threonine-144. SIGNOR-149957 0.2 tertatolol chemical CHEBI:135244 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258862 0.8 PRKDC protein P78527 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser33 ASGDYKYsGRDSLIF 9606 BTO:0001546 26337656 t done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. SIGNOR-274023 0.94 CUL3 protein Q13618 UNIPROT LZTR1 protein Q8N653 UNIPROT up-regulates activity binding 9606 BTO:0000007 31337872 t Gianni Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. SIGNOR-269070 0.273 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. SIGNOR-144465 0.44 TNPO1 protein Q92973 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates activity relocalization 29970603 t lperfetto TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import SIGNOR-262099 0.572 DNA_damage stimulus SIGNOR-ST1 SIGNOR KDM4B protein O94953 UNIPROT up-regulates 9606 30759871 f miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia. SIGNOR-263736 0.7 SP1 protein P08047 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-254218 0.2 CAMK2A protein Q9UQM7 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-275784 0.279 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 0.572 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 0.456 YAP1 protein P46937 UNIPROT CDCA5 protein Q96FF9 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276565 0.2 NOTCH1 protein P46531 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0001271;BTO:0000785 16847353 f gcesareni We identified c-myc as a direct target of notch1 SIGNOR-147944 0.669 TDGF1 protein P13385 UNIPROT MSTN protein O14793 UNIPROT down-regulates 9606 23129614 f fstefani We provide evidence that cripto modulates myogenic cell determination and promotes proliferation by antagonizing the tgf-beta ligand myostatin. SIGNOR-192436 0.312 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 0.292 MMP12 protein P39900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272380 0.7 SRC protein P12931 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates phosphorylation Tyr341 SEEQLQLyWAMDSTF 9606 20525694 t gcesareni Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c. SIGNOR-165862 0.537 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 0.324 MMP13 protein P45452 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu442 TSKGDKElRTGKEKV -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain SIGNOR-263613 0.2 CUDC-101 chemical CID:24756910 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191148 0.8 HAUS2 protein Q9NVX0 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-262323 0.821 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 0.784 DAPK1 protein P53355 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 15616583 t gcesareni Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus. SIGNOR-132610 0.565 TAOK2 protein Q9UL54 UNIPROT STK4 protein Q13043 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-201330 0.279 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser982 VVGANRAsHRAAAPP 9606 BTO:0002181 38307877 t miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  SIGNOR-277917  0.27 SAR1A protein Q9NR31 UNIPROT SEC24B protein O95487 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265300 0.746 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNA7 protein P36544 UNIPROT up-regulates activity chemical activation 27167578 t Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. SIGNOR-253984 0.8 CYP2D6 protein P10635 UNIPROT tyramine smallmolecule CHEBI:15760 ChEBI down-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-263995 0.8 LPAR2 protein Q9HBW0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257324 0.25 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser64 EPDLKKEsEEDKFPV 9606 15889150 t llicata We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta. SIGNOR-137089 0.465 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 0.2 MAPK1 protein P28482 UNIPROT ZFP36 protein P26651 UNIPROT unknown phosphorylation Ser228 PPGDLPLsPSAFSAA 10090 BTO:0000944 7768935 t lperfetto By a combination of protease digestion experiments and site-directed mutagenesis strategies, we found that serine 220 was phosphorylated by p42 MAP kinase in vitro. Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells. |It is not obvious how phosphorylation of TTP at serine 220 would alter DNA binding, since this residue lies well outside of the putative zinc finger region, which is between amino acids 95 to 159 in the mouse protein SIGNOR-249456 0.456 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg707 ESTVMATrKMHDRLE -1 7989361 t lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. SIGNOR-263630 0.601 AKT proteinfamily SIGNOR-PF24 SIGNOR MAPK14 protein Q16539 UNIPROT down-regulates activity 9606 BTO:0000150 12697749 f lperfetto Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1 SIGNOR-244288 0.2 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXRG protein P48443 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-259239 0.8 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 0.8 CDC7 protein O00311 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates activity phosphorylation Ser410 SSMDSKSsGWGM 9606 23424178 t miannu We show CDC7 robustly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. SIGNOR-278257 0.2 SV2A protein Q7L0J3 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 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-264116 0.535 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 BTO:0000150 15156151 t gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 SIGNOR-124856 0.2 COL6A6 protein A6NMZ7 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-254677 0.7 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT down-regulates phosphorylation Thr373 VSMLSLNtPNSNRKR 9606 SIGNOR-C17 16170345 t lperfetto We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341 SIGNOR-140549 0.577 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 0.582 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni We show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2) SIGNOR-139465 0.858 MAP2K1 protein Q02750 UNIPROT 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-236447 0.75 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 11606584 t gcesareni By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk. SIGNOR-111069 0.778 MAPK1 protein P28482 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-113130 0.277 TRIM63 protein Q969Q1 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 f areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy. SIGNOR-254993 0.7 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 8143061 t asthma gcesareni SIGNOR-251706 0.8 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 0.278 Activated PSC phenotype SIGNOR-PH224 SIGNOR ACTA2 protein P62736 UNIPROT up-regulates quantity 9606 BTO:0000988 28232471 t miannu Upon activa- tion, PSCs express the myofibroblast protein α-smooth mus- cle actin (αSMA, gene name Acta2) and secrete factors that stimulate tumor growth, cell survival, and metastasis. As a result of the selective high expression of αSMA, we refer to these periglandular FAP+ αSMAhigh fibroblasts as myofibroblastic CAFs (myCAFs). SIGNOR-277677 0.7 FOXO3 protein O43524 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity transcriptional regulation 10090 BTO:0002314 24749067 f gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. SIGNOR-244076 0.374 STAT3 protein P40763 UNIPROT CD46 protein P15529 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17699108 f miannu The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. SIGNOR-255238 0.268 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 0.8 PLK4 protein O00444 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 t lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap SIGNOR-166007 0.799 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 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-268661 0.8 USF2 protein Q15853 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 f miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. SIGNOR-222608 0.2 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1644 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-248817 0.855 GSK3B protein P49841 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity phosphorylation Ser663 EFDELNPsAQRDACL 9606 BTO:0000562 37291092 t miannu GSK3β-dependent phosphorylation of SERCA2 at serine 663 in human and mouse hearts. Phosphorylation of SERCA2 at serine 663 regulates SERCA2 activity.  SIGNOR-277886 0.283 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 0.646 NFE2L2 protein Q16236 UNIPROT TXN protein P10599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000552 18629308 f miannu When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. SIGNOR-254646 0.404 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH4 protein P55283 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-265844 0.8 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser60 VYQVSRTsGGAGGLG -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro. SIGNOR-100111 0.546 mTORC1 complex SIGNOR-C3 SIGNOR JMJD1C protein Q15652 UNIPROT up-regulates activity phosphorylation Thr505 KFVSRPPtPKCVIDI 9606 BTO:0000007 32034158 t miannu We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding. we detected phosphorylation of WT JMJD1C but not T505A mutant when we co-transfected JMJD1C constructs along with the mTORC1 in 293FT cells SIGNOR-265168 0.242 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 16331690 t The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. SIGNOR-142961 0.408 MMP24 protein Q9Y5R2 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272368 0.7 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser18 EKLQYYYsSSEDEDS 9606 16717095 t lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. SIGNOR-146825 0.387 POMT complex SIGNOR-C372 SIGNOR DGC complex SIGNOR-C217 SIGNOR up-regulates activity glycosylation 9606 BTO:0000007 14699049 t miannu we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain. SIGNOR-265431 0.407 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 9219684 t gcesareni The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. SIGNOR-49477 0.848 EIF4H protein Q15056 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 t Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability SIGNOR-261294 0.802 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 10910062 t AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† SIGNOR-251482 0.2 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248604 0.2 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser82 VDILRKVsGHPNIIQ -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-250389 0.2 RPL17 protein P18621 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-262482 0.764 DDB1 protein Q16531 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR form complex binding 9606 BTO:0000567 9418871 t miannu Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna SIGNOR-54093 0.937 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 0.415 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 0.45 IMPDH1 protein P20839 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267331 0.8 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Thr714 EESDSSEtEKEDDEG 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275502 0.2 CSF1 protein P09603 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 33505964 f miannu  Exosomes from tumor cells package assorted proteins and chemokines with immunomodulatory capability, including CSF-1, CCL2, and TGF-β, to promote M2-like characterization of TAMs SIGNOR-277708 0.7 MTSS1 protein O43312 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t miannu We found that in vitro translated gli1 and sufu bind to gst-mim, but not gst-mim?N399 Or gst columns (fig. 4f). Indicative of the importance of the mim/gli complex interactions, the mim?N399 Mutant that fails to interact with gli and sufu showed a markedly reduced capacity to potentiate gli-dependent transcription (fig. 4g). Although these results indicate that a mim/gli/sufu complex is important for mim-mediated transcriptional potentiation SIGNOR-130545 0.438 GUCY1A2-B2 complex SIGNOR-C137 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244090 0.8 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 29713515 f The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells. SIGNOR-259970 0.7 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 0.324 MYLK2 protein Q9H1R3 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr80 NEPHESRtNSDIVET 9606 BTO:0000007 21556048 t llicata Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis. SIGNOR-238118 0.402 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax SIGNOR-259418 0.2 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni CK2 hyperactivates AKT by phosphorylation at Ser129 SIGNOR-252595 0.372 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 0.709 PTMS protein P20962 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 16150697 t miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner SIGNOR-268460 0.328 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 0.2 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-147963 0.7 PHF1 protein O43189 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260069 0.286 PRKCD protein Q05655 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 t lperfetto Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). SIGNOR-249205 0.306 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 12058066 t lperfetto 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-216845 0.408 CHGA protein P10645 UNIPROT Peptide_hormone_processing phenotype SIGNOR-PH88 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-254275 0.7 FPR2 protein P25090 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256888 0.435 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 0.752 BECN1 protein Q14457 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity binding 9606 BTO:0000567 23478334 t lperfetto We show that Beclin-1 interacts directly with Zwint-1-a component of the KMN (KNL-1/Mis12/Ndc80) complex-which is essential for kinetochore-microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis. SIGNOR-265027 0.435 AKT proteinfamily SIGNOR-PF24 SIGNOR TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 t miannu Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo. SIGNOR-137942 0.2 S100A8 protein P05109 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 t miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner SIGNOR-261937 0.2 IL5 protein P05113 UNIPROT IL5RA protein Q01344 UNIPROT up-regulates binding -1 8567620 t fspada Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor. SIGNOR-40039 0.883 MDM2 protein Q00987 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 BTO:0000567 11070080 t gcesareni Mdm2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins. SIGNOR-84077 0.687 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 0.964 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206361 0.8 STK4 protein Q13043 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity phosphorylation Ser140 GKKATQAsQEY 9606 20921231 t miannu Western blot and kinase assay results with a mutant S139A H2AX confirmed that MST1 phosphorylates H2AX at Ser-139. SIGNOR-278457 0.2 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser40 TQSSGKSsVLESLVG 9606 25192600 t miannu The schematic for GSK3beta phosphorylating Drp1 at Ser 40 and Ser 44 was shown. SIGNOR-278480 0.388 DRD1 protein P21728 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257335 0.495 RPIA protein P49247 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267067 0.8 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 0.8 IL2 protein P60568 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22128144 f miannu We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. SIGNOR-253894 0.35 IL34 protein Q6ZMJ4 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000801 39416792 t miannu CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK SIGNOR-277714 0.912 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-269033 0.2 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271808 0.8 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206358 0.8 SMAD7 protein O15105 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates binding 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-121280 0.679 CDKN1B protein P46527 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 18423396 f fspada Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation. SIGNOR-178278 0.7 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates 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-201935 0.535 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels SIGNOR-105497 0.358 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ -1 15946941 t done miannu PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity SIGNOR-274080 0.2 CREB5 protein Q02930 UNIPROT ATP6V0E1 protein O15342 UNIPROT up-regulates quantity by expression 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-253801 0.2 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser66 GVYATRSsAVRLRSS -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-250068 0.309 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 19623618 t gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. SIGNOR-187209 0.303 TANK protein Q92844 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity binding 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262714 0.734 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21524151 f miannu In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-262532 0.7 PRKCE protein Q02156 UNIPROT NSF protein P46459 UNIPROT up-regulates activity phosphorylation Ser460 MNRHIKAsTKVEVDM 9606 20962217 t miannu PKCepsilon phosphorylation enhances the ATPase activity of NSF.|These results indicate that PKCepsilon phosphorylates NSF at both S460 and T461 in vitro. SIGNOR-278300 0.234 RHOQ protein P17081 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates binding 9606 12687004 t gcesareni Here we show that tc10 interacts with one of the components of the exocyst complex, exo70. SIGNOR-100486 0.636 MAPK1 protein P28482 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-118546 0.561 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 0.75 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 0.2 TRAF6 protein Q9Y4K3 UNIPROT TAB3 protein Q8N5C8 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-205461 0.714 ANK1 protein P16157 UNIPROT SLN protein O00631 UNIPROT down-regulates activity binding 9606 28487373 t lperfetto These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity. SIGNOR-265930 0.257 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 0.8 PPP3CA protein Q08209 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84035 0.508 AKT1 protein P31749 UNIPROT MAPKAP1 protein Q9BPZ7 UNIPROT up-regulates activity phosphorylation Thr86 GIRRRSNtAQRLERL 10090 BTO:0002572 26235620 t miannu Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt. SIGNOR-276932 0.703 DYRK1B protein Q9Y463 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9534 BTO:0000298 14593110 t miannu DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity. SIGNOR-260633 0.258 TSPO2 protein Q5TGU0 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 9606 BTO:0000424 30061676 t miannu Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT. SIGNOR-261826 0.309 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNK18 protein Q7Z418 UNIPROT down-regulates activity phosphorylation Ser252 QAMERSNsCPELVLG -1 18397886 t miannu Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. PKA was used to phosphorylate serine 264 in our further in vitro experiments. SIGNOR-263154 0.2 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser803 QREIQMDsPMLLADL 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259826 0.2 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11486000 t lperfetto Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes. SIGNOR-109647 0.871 PPME1 protein Q9Y570 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates activity demethylation 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 |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. SIGNOR-265750 0.716 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 USF1 protein P22415 UNIPROT GATA5 protein Q9BWX5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22625849 f miannu The present study provides the first evidence that USF1 activates GATA5 gene expression through the E-box motif and suggests a potential mechanism (disruption of the E-box) by which GATA5 promoter methylation reduces GATA5 expression in cancer. SIGNOR-255596 0.334 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 0.381 PPM1B protein O75688 UNIPROT CDK9 protein P50750 UNIPROT unknown dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function SIGNOR-181396 0.372 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 0.8 SH3GLB1 protein Q9Y371 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263886 0.7 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr969 VSECPHTyQNRRPFS 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. SIGNOR-271920 0.2 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser29 QRRSARLsAKPAPPK 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-76324 0.29 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser247 GALSNSEsIPTIDGL 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250599 0.29 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation Ser1279 SRCSSLSsLSSAEDE 9606 BTO:0000038 11487578 t lperfetto Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin. SIGNOR-109660 0.614 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 0.646 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr267 KSNLKRVtLELGGKS -1 28193222 t miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  SIGNOR-276750 0.372 CBLB protein Q13191 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity 9606 BTO:0004175 27773928 f miannu We have also shown that the E3 ubiquitin ligase Cbl-b is crucial for activation of the p53 pathway through ubiquitinating and promoting degradation of Siva1, the E3 ubiquitin ligase targeting ARF, a positive regulator of p53. On the basis of our data presented in the study, we propose the model (Figure 2i) that Cbl-b negatively regulates Siva1 by ubiquitination and subsequent degradation of Siva1, which is followed by stabilization of ARF. This in turn downregulates MDM2, thereby promoting the induction of p53 and activation of its downstream targets. SIGNOR-261320 0.2 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Thr24 TDESLEStRRILGLA 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-249229 0.329 GATA3 protein P23771 UNIPROT CEBPA protein P49715 UNIPROT down-regulates binding 9606 17139329 t fferrentino Whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBPα to inhibit its transcriptional activity on the Pparg2 promoter. SIGNOR-250569 0.361 NFIA protein Q12857 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268872 0.2 CDH4 protein P55283 UNIPROT CDH15 protein P55291 UNIPROT down-regulates quantity by repression 10090 BTO:0000165 18701479 f lperfetto Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts. SIGNOR-253106 0.415 KHSRP protein Q92945 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000130;BTO:0000876 2848118 t gcesareni Ksrp was shown to interact with the c-terminus of dvl3. We show that ksrp negatively regulates wnt/beta-catenin signaling at the level of post-transcriptional ctnnb1 (beta-catenin) mrna stability. SIGNOR-23800 0.2 FOXJ1 protein Q92949 UNIPROT TEKT1 protein Q969V4 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-266936 0.364 PAK1 protein Q13153 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 12198493 t gcesareni In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152. SIGNOR-92065 0.789 GTF3C3 protein Q9Y5Q9 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266186 0.881 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276892 0.451 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 0.2 orantinib chemical CHEBI:91088 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207438 0.8 RBSN protein Q9H1K0 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto Rabenosyn-5 is another FYVE-domain-containing Rab5 effector that localizes to EE SIGNOR-260624 0.2 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 0.348 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 11960013 t lperfetto In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1. SIGNOR-117315 0.687 TNFRSF21 protein O75509 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni Dr6 interacts with tradd SIGNOR-100184 0.581 RAB14 protein P61106 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260619 0.433 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 0.7 LYST protein Q99698 UNIPROT RAB5A protein P20339 UNIPROT down-regulates activity binding 7227 33725482 t lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment SIGNOR-266001 0.266 JAK2 protein O60674 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation 9606 10938266 t miannu Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. SIGNOR-279197 0.623 LPAR3 protein Q9UBY5 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257357 0.5 MECOM protein Q03112 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 21695170 t lperfetto The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA|Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. SIGNOR-273432 0.293 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 0.2 PML protein P29590 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0001271 15093545 f gcesareni The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor SIGNOR-256659 0.7 PHA-848125 chemical CID:16718576 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206151 0.8 PAK1 protein Q13153 UNIPROT BCL6 protein P41182 UNIPROT down-regulates activity phosphorylation 9606 22723377 t miannu The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1. SIGNOR-253930 0.2 AKT1 protein P31749 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Ser516 KTSSRRSsMSMEETE 9606 BTO:0002181 27702651 t miannu We found that AKT phosphorylates MITF at S510. Phosphorylated MITF S510 enhances its affinity to TP53 and promotes CDKN1A expression. Phosphorylation of MITF by AKT induces its degradation SIGNOR-277281 0.44 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 11733498 t lperfetto Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1. SIGNOR-112549 0.2 NCBP1 protein Q09161 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 BTO:0001413 11483597 t miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222939 0.2 BTG2 protein P78543 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity binding 9606 BTO:0000093 22493435 t miannu BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity. SIGNOR-254647 0.2 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 20603078 t miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. SIGNOR-273845 0.721 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-236436 0.817 ACE2 protein Q9BYF1 UNIPROT Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260227 0.2 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 t gcesareni Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells. SIGNOR-98267 0.415 MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax SIGNOR-149774 0.625 AKAP13 protein Q12802 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-260527 0.744 ATP5ME protein P56385 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-261407 0.2 CDK5 protein Q00535 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Thr733 LPPVFSGtPKGSGAG 9606 27735944 t miannu CDK5 directly phosphorylated ERK5 at Thr732 and modulated the ERK5\u2013AP-1 signaling axis. SIGNOR-279364 0.2 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 0.2 PPP2R2B protein Q00005 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity binding 9606 21075311 t gcesareni Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. SIGNOR-243511 0.331 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0003316 11777913 t miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. SIGNOR-250098 0.433 STUB1 protein Q9UNE7 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17239458 t miannu The ErbB2 kinase domain is required for GA-induced and CHIP-dependent ErbB2 ubiquitination and degradation . SIGNOR-278645 0.627 YAP1 protein P46937 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230719 0.942 NRCAM protein Q92823 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266720 0.721 GSK3B protein P49841 UNIPROT MUC1 protein P15941 UNIPROT down-regulates activity phosphorylation Ser1227 PPSSTDRsPYEKVSA BTO:0000567 9819408 t lperfetto GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo. SIGNOR-249356 0.456 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 16420481 t The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. SIGNOR-143841 0.406 tiotropium chemical CHEBI:90960 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition -1 8441333 t miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. SIGNOR-258485 0.8 CAMKK1 protein Q8N5S9 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-176598 0.462 DNM1 protein Q05193 UNIPROT MYO1E protein Q12965 UNIPROT up-regulates activity binding 10116 BTO:0000142 17257598 t miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. SIGNOR-265424 0.333 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-22420 0.553 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 0.776 KRAS protein P01116 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here SIGNOR-249585 0.648 SPTAN1 protein Q13813 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 9624143 f Cleaved by CASP3 amattioni A-fodrin cleavage contributes to blebbing SIGNOR-57897 0.7 PRKCA protein P17252 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Ser76 VQDTSGTsPVHDAAR 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. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation. SIGNOR-197285 0.2 DHX30 protein Q7L2E3 UNIPROT FASTKD2 protein Q9NYY8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25683715 f miannu DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1. SIGNOR-261225 0.383 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation Ser480 PVPHSGSsGYGSLGS -1 30425162 t miannu Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2 SIGNOR-277419 0.902 AMPK complex SIGNOR-C15 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity phosphorylation 9606 23863160 t lperfetto Under energy deprivation, AMPK positively regulates ULK1 to induce autophagy, with various studies revealing that AMPK binds to and phosphorylates ULK1 SIGNOR-209913 0.433 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 0.443 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-252920 0.2 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs SIGNOR-235745 0.755 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.752 GTF2A1 protein P52655 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR form complex binding 9606 BTO:0000567 7724559 t lperfetto TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. SIGNOR-266197 0.94 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-122062 0.696 SIRT1 protein Q96EB6 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 20713551 f miannu Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. SIGNOR-255139 0.257 FGF14 protein Q92915 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253437 0.258 YWHAQ protein P27348 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11433030 t gcesareni 14-3-3tau associates with and activates the mef2d transcription factor during muscle cell differentiation. SIGNOR-109139 0.583 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235495 0.788 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr795 FPNTEPFyAAFGNRP 9606 BTO:0002181 33203880 t miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. SIGNOR-277291 0.2 C1D protein Q13901 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates activity binding 9606 BTO:0000567 9405624 t 2 miannu SUN-CoR is a protein involved in transcriptional repression by nuclear hormone receptors. The C terminus of SUN-CoR interacts with TR and RevErb in vitro and associates with RevErb in cells, SUN-CoR potentiates repression by both receptors in cells, and the N terminus of SUN-CoR contains an intrinsic repression domain. SIGNOR-241272 0.314 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 0.537 SMARCC1 protein Q92922 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-269824 0.836 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 0.463 CBLB protein Q13191 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates quantity ubiquitination 9606 35288194 t miannu Cbl-b modulated TrkA ubiquitination and function in the dorsal root ganglion of mice.|Viral expression of constitutively active Cbl-b in DRGs of osteoarthritic mice effectively repressed TrkA protein level and more importantly, alleviated mechanical allodynia and heat hyperalgesia. SIGNOR-278690 0.276 S100A9 protein P06702 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 f miannu S100A9 induces differentiation of acute myeloid leukemia cells through TLR4. SIGNOR-261922 0.7 TG101209 chemical CHEBI:90304 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207266 0.8 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207672 0.8 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 0.2 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. SIGNOR-85175 0.339 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation SIGNOR-252981 0.517 DYRK1A protein Q13627 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR 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-254313 0.396 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr531 HEEDADSyENMDNPD 10090 BTO:0000776 10933394 t lperfetto Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni SIGNOR-249377 0.772 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT up-regulates activity phosphorylation Tyr986 QRQPFVKyATLISNS 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263493 0.774 CTTN protein Q14247 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting. SIGNOR-266595 0.7 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 0.2 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t Epiregulin may be a mediator of localized cell proliferation gcesareni Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. SIGNOR-165782 0.892 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 0.7 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates quantity by stabilization phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 t Manara ASK2 Activates ASK1 by Phosphorylation SIGNOR-260832 0.551 GPC6 protein Q9Y625 UNIPROT WNT5A protein P41221 UNIPROT down-regulates activity binding 9606 BTO:0000007 31756413 t miannu GPC6 binds to Wnt5a and inhibits its release from producing cells. Based on theseresults, and in our finding that GPC6 inhibits non-canonical Wnt signaling in the developing intestine,we tested the hypothesis that GPC6 binds to Wnt5aat the surface of the Wnt5a-producing mesenchymalcells and restrains its release from them. SIGNOR-264030 0.374 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175825 0.636 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 0.2 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 22334659 t gcesareni Phosphorylation at thr-116 and thr-226 of orc2 occurs by cyclin-dependent kinase during the s phase and is maintained until the m phase. Phosphorylation of orc2 at thr-116 and thr-226 dissociated the orc2-5 from chromatin. SIGNOR-196048 0.756 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr806 PLLLIVEyAKYGSLR 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation. SIGNOR-121153 0.2 SLC19A1 protein P41440 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity relocalization 9606 10787414 t lperfetto The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells. SIGNOR-268266 0.8 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 0.8 NFIB protein O00712 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-268878 0.2 RLIM protein Q9NVW2 UNIPROT LDB1 protein Q86U70 UNIPROT down-regulates quantity by destabilization polyubiquitination 10029 BTO:0000246 11882901 t miannu Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.  SIGNOR-272617 0.566 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 0.484 PRKCA protein P17252 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202780 0.2 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236483 0.2 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-143688 0.637 CGRRF1 protein Q99675 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002548 31801577 t miannu CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation. SIGNOR-272220 0.2 ITGB2 protein P05107 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253192 0.754 IL20RA protein Q9UHF4 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000782;BTO:0000876 12941475 f gcesareni Il-20 induces cheratin proliferation and stat-3 signal transduction pathway SIGNOR-86269 0.582 ETV2 protein O00321 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0001086 24583263 f irozzo Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation. SIGNOR-256009 0.7 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10966616 t gcesareni Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr) SIGNOR-81379 0.791 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 0.443 HDAC4 protein P56524 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 BTO:0000887 10737771 t gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. SIGNOR-76231 0.564 p38 proteinfamily SIGNOR-PF16 SIGNOR DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation -1 8650547 t Luana Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase SIGNOR-260724 0.2 N-hydroxy-1-[(4-methoxyphenyl)methyl]-6-indolecarboxamide chemical CHEBI:94192 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189684 0.8 SKP1 protein P63208 UNIPROT CUL1 protein Q13616 UNIPROT up-regulates binding 9606 10023660 t gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. SIGNOR-64511 0.959 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 0.308 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 25086053 t lperfetto Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions, SIGNOR-205247 0.331 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275508 0.325 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 21454478 t gcesareni In addition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r/co-smad complex and further promoting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner SIGNOR-172996 0.343 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 t lperfetto Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. 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 SIGNOR-144787 0.877 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 0.323 AP2M1 protein Q96CW1 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19351721 t gcesareni The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr. SIGNOR-185124 0.524 RIMS3 protein Q9UJD0 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-264379 0.282 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 0.681 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 0.69 BTG2 protein P78543 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254648 0.2 CREB1 protein P16220 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity binding 9606 15126506 t lperfetto We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity SIGNOR-252894 0.514 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227521 0.448 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser165 RESSLSPsPASSISS 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-53368 0.711 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260629 0.523 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000782 15851487 t lperfetto Baff specifically binds baff receptor SIGNOR-135713 0.785 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 11847341 t lperfetto Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha. SIGNOR-114843 0.823 CUL2 protein Q13617 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-268845 0.31 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 0.2 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 0.2 EXOC4 protein Q96A65 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270787 0.959 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t The effect has been demonstrated using Q08499-2 llicata Long pde4d forms are inhibited by erk2 phosphorylation SIGNOR-77574 0.353 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea chemical CHEBI:124917 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193787 0.8 GATA1 protein P15976 UNIPROT ZFPM1 protein Q8IX07 UNIPROT up-regulates activity binding 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-256059 0.798 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 0.549 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 f It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils SIGNOR-254351 0.395 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 0.2 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 0.8 DVL2 protein O14641 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 t areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin SIGNOR-258979 0.268 SMARCD1 protein Q96GM5 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269785 0.669 acalabrutinib chemical CHEBI:167707 ChEBI BTK protein Q06187 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0006414 35597428 t Marta Tosoni As expected, ibrutinib and acalabrutinib also inhibited autophosphorylation of BTK (on Y223) SIGNOR-278086 0.8 BTK protein Q06187 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation 9606 31431692 t miannu Then, BTK and ITK are activated by Src kinases and proceed to phosphorylate the lipase PLCgamma2 / PLCgamma1, which cleaves PIP2 in the plasma membrane and generates the secondary messengers IP3 and DAG. SIGNOR-279444 0.581 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100181 0.312 TSC complex SIGNOR-C101 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor SIGNOR-217907 0.777 DERA protein Q9Y315 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267098 0.8 DLX5 protein P56178 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates -1 19195802 f Luana DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis. SIGNOR-265797 0.7 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275714 0.7 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 0.456 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 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-201290 0.817 metoprolol chemical CHEBI:6904 ChEBI ADRB1 protein P08588 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 t Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue SIGNOR-258337 0.8 PIK3R4 protein Q99570 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260321 0.884 MAP3K7 protein O43318 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser463 SPHNPISsVS 9606 19536134 t miannu This analysis showed that phosphorylation of Smad1 at the C-terminal serines S463 and S465 was increased by co-expression of constitutively active TAK1. SIGNOR-279419 0.373 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 t lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites SIGNOR-131375 0.611 RPS6KB1 protein P23443 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates 10090 BTO:0002572 20670887 f lperfetto We find that srebp1 and 2 promote proliferation downstream of mtorc1, and the activation of these transcription factors is mediated by s6k1. SIGNOR-167190 0.424 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI up-regulates quantity precursor of 9606 20490924 t miannu VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2 SIGNOR-280308 0.8 FHIT protein P49789 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates 9606 BTO:0000551 15313915 f miannu We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein. SIGNOR-127610 0.428 MYC protein P01106 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 9606 19786833 t irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255806 0.712 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507-3 UNIPROT down-regulates phosphorylation Thr11 SPSLRRMtVMREKGR 9606 BTO:0000007 16331690 t The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. SIGNOR-142957 0.408 EFNA1 protein P20827 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 17420126 t gcesareni Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells. SIGNOR-154298 0.817 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 18344021 t apalma Two ADAMs have been implicated in the S2 cleavage of Notch. In Drosophila, ADAM10 ortholog Kuzbanian is the main protease mediating Notch processing [35–38]. In mouse cells in vitro, ADAM17, and not ADAM10, appears to be a protease responsible for Notch cleavage SIGNOR-255370 0.739 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 0.398 PLK1 protein P53350 UNIPROT STK3 protein Q13188 UNIPROT down-regulates activity phosphorylation Ser15 KSKLKKLsEDSLTKQ 9606 BTO:0002181 37739411 t miannu  We conclude that TRIM69A promotes multi-site phosphorylation of MST2.We demonstrate that TRIM69 stimulates formation of an MST2-PLK1 complex and promotes phosphorylation of MST2 at S15, a known PLK1 site. PLK1-mediated MST2 phosphorylation at S15 is necessary for subsequent phosphorylation of NEK2A to dissociate c-NAP1 from daughter centrioles (7). Thus, we provide a new molecular mechanism by which TRIM69 promotes MST2- and PLK1-mediated centrosome disjunction. SIGNOR-277904 0.331 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 27660409 t diabetic macular edema gcesareni They differ according to their glucocorticoid-receptor binding affinities (dexamethasone > triamcinolone > fluocinolone) and their lipophilicity (triamcinolone > fluocinolone > dexamethasone), characteristics that may partially explain their relative potencies SIGNOR-251694 0.8 Dinaciclib chemical CID:46926350 PUBCHEM CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191328 0.8 PRKACA protein P17612 UNIPROT KCNK9 protein Q9NPC2 UNIPROT up-regulates phosphorylation Ser373 RLMKRRKsV 9606 BTO:0000007 21357689 t llicata Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression. SIGNOR-172466 0.2 MAPK11 protein Q15759 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 17254968 t gcesareni We show that prak activates p53 by direct phosphorylation. SIGNOR-152843 0.611 STOML2 protein Q9UJZ1 UNIPROT OPA1 protein O60313 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f Giorgia Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion. SIGNOR-260381 0.312 MAPKAPK2 protein P49137 UNIPROT PARN protein O95453 UNIPROT down-regulates phosphorylation Ser557 NHYYRNNsFTAPSTV 9606 20932473 t lperfetto Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site. SIGNOR-168377 0.375 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 0.8 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-217403 0.869 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 0.8 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 0.681 ADX-47273 chemical CID:11383075 PUBCHEM GRM5 protein P41594 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189338 0.8 EID1 protein Q9Y6B2 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates activity binding 11073989 t lperfetto Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. SIGNOR-253380 0.406 EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000150 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-235692 0.879 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr187 KRNTVIGtPFWMAPE 9534 BTO:0004055 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. SIGNOR-247581 0.2 B4GALT1 protein P15291 UNIPROT UDP-D-galactose smallmolecule CHEBI:18307 ChEBI down-regulates quantity chemical modification 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268467 0.8 TCL1B protein O95988 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation. SIGNOR-81716 0.56 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser474 HFPQFSYsASGRE 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-248609 0.494 SH2B3 protein Q9UQQ2 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22101255 f miannu Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli. SIGNOR-177485 0.2 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 0.2 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 0.574 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 0.67 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 0.486 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT down-regulates activity phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 14613924 t miannu ACCβ(Ser221) is a known target for AMPK in human skeletal muscle SIGNOR-250316 0.649 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 0.517 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 0.894 veliparib chemical CHEBI:62880 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189183 0.8 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE 9606 11278496 t lperfetto TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels SIGNOR-246634 0.678 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 9606 16286470 t lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-141605 0.786 STK38 protein Q15208 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity phosphorylation Ser277 RTHQRSKsDATASIS 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263033 0.267 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 t The effect has been demonstrated using Q08499-5 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-77571 0.353 NUP54 protein Q7Z3B4 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 t Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. SIGNOR-261259 0.94 DPM complex complex SIGNOR-C289 SIGNOR dolichyl beta-D-mannosyl phosphate smallmolecule CHEBI:17624 ChEBI up-regulates quantity chemical modification 9606 10835346 t lperfetto Dolichol-phosphate-mannose (DPM) synthase generates mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation. SIGNOR-262566 0.8 DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17335796 f gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. SIGNOR-153454 0.484 HCRTR2 protein O43614 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-256872 0.264 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 0.475 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr740 RNLYSGDyYRIQGRA 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-140763 0.38 ATG12/5/16L1 complex SIGNOR-C109 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates -1 23321721 f lperfetto Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation SIGNOR-226702 0.7 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. SIGNOR-74931 0.552 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr325 AISEELPySEYFEYF -1 30317579 t miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  SIGNOR-277484 0.385 MAPK1 protein P28482 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr507 GLGENLLtHLPEEIG 9606 BTO:0000007 30865892 t miannu Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. SIGNOR-277442 0.322 acetyl-CoA smallmolecule CHEBI:15351 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates activity 9606 10893421 f Acetyl-CoA carboxylase (ACC) catalyzes the first committed step of the fatty acid synthetic pathway. Although ACC has often been proposed to be a major rate-controlling enzyme of this pathway, no direct tests of this proposal in vivo SIGNOR-267383 0.7 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-252962 0.595 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 0.8 PRKCG protein P05129 UNIPROT STK17B protein O94768 UNIPROT down-regulates activity phosphorylation Ser351 PEDSSMVsKRFRFDD 10090 BTO:0000944 18084041 t miannu These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS. Ectopic expression of PKC-gamma induced cytoplasmic localization of DRAK2 and PKC-gamma phosphorylated Ser350 flanking the NLS. SIGNOR-263178 0.2 BUD13 protein Q9BRD0 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270672 0.521 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 0.674 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 16809543 t amattioni Dek phosphorylated at serines 19 and 32. Dek and its phosphorylation are required for intron removal SIGNOR-147365 0.35 MYC protein P01106 UNIPROT HLA-F protein P30511 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254605 0.2 DYRK3 protein O43781 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 23415227 t lperfetto When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40 SIGNOR-201002 0.34 CDC42 protein P60953 UNIPROT GSK3B protein P49841 UNIPROT down-regulates binding 9606 14657655 t gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. SIGNOR-119885 0.377 PLCE1 protein Q9P212 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152771 0.8 regorafenib chemical CHEBI:68647 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259177 0.8 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells. SIGNOR-115831 0.796 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. SIGNOR-90832 0.413 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 16943190 t lperfetto we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human SIGNOR-149277 0.419 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT down-regulates activity acetylation Lys18 LESDTAMkKGETLRK 28790157 t lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. SIGNOR-275902 0.245 WNK4 protein Q96J92 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Thr231 TRNKVRKtFVGTPCW 16990453 t lperfetto Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 SIGNOR-264640 0.507 UBR2 protein Q8IWV8 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates quantity ubiquitination 9606 23408894 t miannu Mub1 and Ubr2 mediate Dsn1 ubiquitylation and degradation.|The levels of WT Dsn1 were also increased in the mub1Delta and ubr2Delta strains, suggesting that Mub1 and Ubr2 mediate the degradation of WT Dsn1 protein. SIGNOR-278795 0.2 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 0.2 TRIM39 protein Q9HCM9 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 23213260 t miannu Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. SIGNOR-272020 0.351 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT up-regulates transcriptional regulation 10116 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-210149 0.684 ANXA1 protein P04083 UNIPROT FPR3 protein P25089 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 t We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. SIGNOR-259438 0.618 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 0.7 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr447 SEELDENyVPMNPNS 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-236420 0.76 EZH2 protein Q15910 UNIPROT SSTR1 protein P30872 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 f miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. SIGNOR-254143 0.2 OPRK1 protein P41145 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-256853 0.459 GNA12 protein Q03113 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-256516 0.631 WWTR1 protein Q9GZV5 UNIPROT LTBR protein P36941 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22470139 f miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. SIGNOR-255604 0.2 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 11459935 t gcesareni Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T SIGNOR-235150 0.726 FADS6 protein Q8N9I5 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267910 0.8 CBLB protein Q13191 UNIPROT STAT6 protein P42226 UNIPROT down-regulates quantity ubiquitination Lys108 QILQGEKkAVMEQFR 9606 24508458 t miannu Having shown that Cbl-b negatively regulates Stat6, we further investigated the mechanism of this regulation by determining whether Cbl-b associates with Stat6.|Our data demonstrate that Stat6 is ubiquitinated at K108 and K398 by Cbl-b, and that Stat6 ubiquitination is a critical post-translational regulatory mechanism for Stat6. SIGNOR-278805 0.2 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM 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-257914 0.8 POU2F1 protein P14859 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-254432 0.2 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS2 protein Q9NRM7 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-198553 0.8 ISYNA1 protein Q9NPH2 UNIPROT 1D-myo-inositol 1-phosphate smallmolecule CHEBI:18297 ChEBI up-regulates quantity chemical modification 9606 15464731 t lperfetto Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate. SIGNOR-254131 0.8 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 0.928 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 0.8 SEPTIN9 protein Q9UHD8 UNIPROT ARHGEF18 protein Q6ZSZ5 UNIPROT down-regulates binding 9606 15558029 t miannu In transient expression analyses, sept9b inhibited sa-rhogef-dependent rho activation in cos7 and hela cells. SIGNOR-131184 0.2 RNF8 protein O76064 UNIPROT H1-2 protein P16403 UNIPROT down-regulates polyubiquitination 9606 BTO:0000815 30517763 t miannu ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. SIGNOR-272928 0.2 PRKCQ protein Q04759 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser323 LCLQKDPsKRPTAAE -1 14988727 t miannu Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. SIGNOR-276007 0.487 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 t gcesareni Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation. SIGNOR-113776 0.8 DUSP7 protein Q16829 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues SIGNOR-166577 0.657 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K12 protein Q12852 UNIPROT down-regulates binding 9606 11432832 t gcesareni Jip inhibits dlk dimerization. SIGNOR-109046 0.516 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 0.7 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 0.8 zotepine chemical CHEBI:32316 ChEBI ADRA2B protein P18089 UNIPROT down-regulates activity chemical inhibition 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258559 0.8 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 0.271 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu54 EMKKGHLeRECMEET -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-263666 0.615 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269377 0.726 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 10993892 t gcesareni Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation. SIGNOR-82083 0.474 MECP2 protein P51608 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0004102 18952054 t Luana The interaction of MeCP2 with the 2BI3 and 2BI5 sites was strikingly reduced in neurons maintained in the presence of TTX (Fig. 2C). This result is consistent with the classical view of MeCP2 as a general transcriptional repressor, in that the reduced association leads to increased expression of NR2B. SIGNOR-264685 0.35 RIPK1 protein Q13546 UNIPROT Necrosis phenotype SIGNOR-PH3 SIGNOR up-regulates 9606 14965271 f amattioni Fas-induced necrosis requires rip SIGNOR-121901 0.7 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 0.606 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 0.661 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser537 DNSMSVPsPTSATKT 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268338 0.258 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-265810 0.8 RASGEF1C protein Q8N431 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-161505 0.2 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266946 0.8 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT up-regulates activity phosphorylation Tyr99 RGRYRSPySGPKFNS 9606 BTO:0000007 27018250 t miannu In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. SIGNOR-262610 0.322 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC4R protein P32245 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-257538 0.8 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development. SIGNOR-266979 0.477 AR protein P10275 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16697957 t miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. SIGNOR-251546 0.502 SRC protein P12931 UNIPROT SDHA protein P31040 UNIPROT up-regulates activity phosphorylation Tyr215 SLRYDTSyFVEYFAL 9606 BTO:0001583 22823520 t miannu Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants.  SIGNOR-276420 0.267 CCNO protein P22674 UNIPROT CDK13 protein Q14004 UNIPROT up-regulates activity binding 37197505 t lperfetto Cyclin O promotes lung cancer progression and cetuximab resistance via cell cycle regulation and CDK13 interaction|CCNO promoted tumor cell proliferation and survival in vivo via CDK13| SIGNOR-275618 0.271 ABL1 protein P00519 UNIPROT AHSA1 protein O95433 UNIPROT up-regulates activity phosphorylation Tyr223 LTSPEELyRVFTTQE 9606 26235616 t Manara Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity SIGNOR-260938 0.251 SOCS3 protein O14543 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates 9606 16543409 f lperfetto Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown SIGNOR-253052 0.391 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR -1 9614189 t miannu S214 can be rapidly and selectively phosphorylated in vitro by PKA, and this single site strongly affects tau's ability to bind and stabilize microtubules. SIGNOR-250006 0.433 PTPRF protein P10586 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11121408 t gcesareni Here we show that lar reduces the constitutive tyrosine autophosphorylation and kinase activity of ret-men2a but not ret-men2b, accompanying a significant decrease of phosphorylation of phospholipase cgamma, akt, and erk1/2. SIGNOR-85166 0.2 PTP4A2 protein Q12974 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation 9606 14643450 t amattioni Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity SIGNOR-119478 0.2 XAF1 protein Q6GPH4 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 17613533 t gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3. SIGNOR-155637 0.558 ibuprofen chemical CHEBI:5855 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258604 0.8 PKI-587 chemical CID:44516953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205992 0.8 FGR protein P09769 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 t miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  SIGNOR-276725 0.2 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 0.617 AMPK complex SIGNOR-C15 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 10116 21892142 t lperfetto AMPK has also been suggested to phosphorylate the glucose-sensitive transcription factor ChREBP89 which dictates expression of an overlapping lipogenic gene signature with Srebp1 SIGNOR-216561 0.431 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 12897152 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-104493 0.835 SMARCA2 protein P51531 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65435 0.9 SFPQ protein P23246 UNIPROT NONO/SFPQ complex SIGNOR-C62 SIGNOR form complex binding 9606 9756848 t miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i SIGNOR-60560 0.711 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270404 0.8 CDK1 protein P06493 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR form complex binding 9606 29870721 t lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. SIGNOR-267570 0.922 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 0.633 PTEN protein P60484 UNIPROT PTK6 protein Q13882 UNIPROT down-regulates activity dephosphorylation Tyr342 RLIKEDVyLSHDHNI -1 29142193 t lperfetto PTEN inhibits PTK6 activity and downstream signaling in prostate cancer cells.|Using an in vitro phosphatase assay, we observed that PTEN was able to dephosphorylate PTK6 at tyrosine residue 342 in a dose dependent manner. SIGNOR-276975 0.416 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 t lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-217469 0.611 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser664 IDPGADLsQYKMDVT 9606 BTO:0000150 10910365 t llicata Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45 SIGNOR-79872 0.828 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 0.793 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 0.599 ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-255545 0.8 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 0.307 ABL1 protein P00519 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 t miannu Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.  SIGNOR-276641 0.268 Exon junction complex complex SIGNOR-C369 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 11532962 t lperfetto The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay SIGNOR-268315 0.8 CREBRF protein Q8IUR6 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16940180 t Luana Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element. SIGNOR-261575 0.2 mTORC2 complex SIGNOR-C2 SIGNOR FBXW8 protein Q8N3Y1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser85 DVASRSRsPLAREGA 10090 BTO:0002572 23142081 t miannu MTORC2 stabilizes Fbw8 by phosphorylation at Ser86 SIGNOR-271940 0.264 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 0.822 PKN1 protein Q16512 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni Phosphorylation of mltkalpha by pknalpha enhances its kinase activity SIGNOR-152768 0.2 SB-202190 chemical CHEBI:79090 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206697 0.8 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM3A protein Q9Y4C1 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-273479 0.8 PRKCQ protein Q04759 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS 9606 BTO:0000782 16479000 t miannu PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells. SIGNOR-276045 0.2 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser536 GRGSKRLsRSVTMRK 9606 24505490 t llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. SIGNOR-204546 0.2 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser1138 PSITKQHsQTPSTLN -1 14970204 t miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. SIGNOR-262688 0.429 AKT1 protein P31749 UNIPROT 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-252530 0.2 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser166 EPRSRHLsVSSQNPG 9534 BTO:0001538 12392720 t miannu It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3. SIGNOR-250004 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser363 LKNKTESsLLAKLEE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276209 0.2 CEBPA protein P49715 UNIPROT HAMP protein P81172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18671304 f miannu HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter. SIGNOR-253770 0.297 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 0.421 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164675 0.2 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 0.8 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling. SIGNOR-48677 0.442 CSNK1A1 protein P48729 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates phosphorylation Ser19 MIPKSSFsINSLVPE 9606 BTO:0000938 BTO:0000142 17435750 t llicata Cki phosphorylation of ser 19 of foxg1 promotes nuclear import SIGNOR-154386 0.2 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 0.7 episterol ester smallmolecule CHEBI:52393 ChEBI CNR1 protein P21554 UNIPROT up-regulates activity chemical activation 9606 BTO:0000142 29751000 t miannu 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. SIGNOR-264266 0.8 PITX2 protein Q99697 UNIPROT TBX1 protein O43435 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20129917 f Regulation miannu Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression. SIGNOR-251870 0.42 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR form complex binding 9606 8893010 t ggiuliani Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta. SIGNOR-255774 0.671 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser360 RKTQTSMsLGTTREK -1 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266440 0.753 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269328 0.435 PCM1 protein Q15154 UNIPROT PCNT protein O95613 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-95117 0.688 PCDH19 protein Q8TAB3 UNIPROT GABRA4 protein P48169 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C327,SIGNOR-C326,SIGNOR-C333 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267220 0.2 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 9388184 t lperfetto PIAS3 blocked the DNA- binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3. SIGNOR-238648 0.731 PAK4 protein O96013 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization phosphorylation Ser465 SPSVRCSsMS 9606 23934187 t miannu In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. SIGNOR-279084 0.339 TRIM26 protein Q12899 UNIPROT NTHL1 protein P78549 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29610152 t miannu We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation. SIGNOR-278733 0.263 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr74 TRGDADMyDLPKKED 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-188312 0.451 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 0.947 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189993 0.8 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 0.7 PLK1 protein P53350 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser289 SDENKENsFSADHVT 9606 20615875 t lperfetto We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner SIGNOR-166564 0.275 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 0.2 CAMK2G protein Q13555 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser19 KGFRRAVsELDAKQA 1680128 t llicata  In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. | Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine. SIGNOR-250709 0.332 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17157787 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-151134 0.354 ramipril chemical CHEBI:8774 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 6097265 t miannu 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl] - (1S,3S,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (Hoe 498) is a new, very effective and long lasting, nonsulfhydryl angiotensin I converting enzyme inhibitor. SIGNOR-258400 0.8 DDC protein P20711 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal SIGNOR-263992 0.8 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 0.321 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194631 0.8 WNT7A protein O00755 UNIPROT MMP10 protein P09238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003137 29549123 t Marta Tosoni We first proved that Wnt7a activated the canonical Wnt pathway through direct regulation of the MMP10 gene. SIGNOR-278867 0.2 WNT7A protein O00755 UNIPROT MMP1 protein P03956 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003137 29549123 t Marta Tosoni Because MMP1 is also another direct target of the canonical Wnt pathway (22), Wnt7a overexpression upregulated MMP1/10 to degrade the extracellular matrix and to facilitate UBC cell invasion. SIGNOR-278868 0.261 GRK6 protein P43250 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 30936203 f Marta Tosoni Taken together, our data suggest that GRK6 contributes to CXCR4 degradation by facilitating ubiquitination of CXCR4. SIGNOR-278869 0.563 NPFFR2 protein Q9Y5X5 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0000608 36497331 f Marta Tosoni NPFFR2 activation by the NPFF peptide also increased cell migration in SNU739 cells. SIGNOR-278870 0.7 NPFFR2 protein Q9Y5X5 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR up-regulates 9606 BTO:0000608 36497331 f Marta Tosoni NPFFR2 Increases Invasiveness and Migration in HCC Cancer Cells SIGNOR-278871 0.7 LPAR6 protein P43657 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0000578 23182454 t Marta Tosoni LPAR1 is reported to associate with Gia,G12/13a,orGqa; LPAR3 with Gia or Gqa; and LPAR6 withGia,G12/13a,orGsa. SIGNOR-278872 0.323 LPAR6 protein P43657 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000578 23182454 t Marta Tosoni LPAR1 is reported to associate with Gia,G12/13a,orGqa; LPAR3 with Gia or Gqa; and LPAR6 withGia,G12/13a,orGsa. SIGNOR-278873 0.323 WNT7A protein O00755 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000972 31886205 f Marta Tosoni These results suggest that Wnt7a represses growth of liver cancer Hep3B cells. SIGNOR-278874 0.7 WNT7A protein O00755 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0000972 31886205 f Marta Tosoni Wnt7a Protein Inhibits Migration of HCC Cells by Downregulating EMT SIGNOR-278875 0.7 GNAI1 protein P63096 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR down-regulates 9606 BTO:0003191 23691483 t Marta Tosoni GNAI1 can signifi cantly inhibit the migration and metastasis of HCC cells. SIGNOR-278877 0.7 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates 9606 19491292 f gcesareni Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment. SIGNOR-252970 0.581 PRKCZ protein Q05513 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser144 GDVGALEsLRGNADL 9606 16287866 t gcesareni Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta). SIGNOR-141629 0.348 BBOX1 protein O75936 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269698 0.8 vatalanib chemical CHEBI:90620 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207648 0.8 CEBPB protein P17676 UNIPROT PCK2 protein Q16822 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000608 8093246 f miannu C/EBP beta can regulate PEPCK gene transcription by acting through the CRE and that C/EBP beta, together with CREB, may contribute to the cAMP responsiveness of the PEPCK promoter. SIGNOR-253773 0.327 GNAO1 protein P09471 UNIPROT CREB1 protein P16220 UNIPROT down-regulates 9606 BTO:0006001 39580518 f Marta Tosoni These data demonstrate that GNAO1 overexpression decreases CREB protein expression SIGNOR-278886 0.247 HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates activity binding -1 37450419 t Marta Tosoni Activation of MET by HGF. MET and HGF form the asymmetric 2 : 2 complex. The dimeric METundergoes autophosphorylation and activates downstream signaling pathways, leading to cellular responses SIGNOR-278887 0.928 GNAO1 protein P09471 UNIPROT TRIM21 protein P19474 UNIPROT down-regulates 9606 BTO:0006001 39580518 t Marta Tosoni Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination.  SIGNOR-278888 0.2 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr666 GWMEDYDyVHLQGKE 11604500 t lperfetto FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD. SIGNOR-249112 0.811 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 17151142 f [...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation SIGNOR-253600 0.371 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI GRM3 protein Q14832 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-193772 0.8 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR 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-254306 0.2 LCK protein P06239 UNIPROT PRKCQ protein Q04759 UNIPROT unknown phosphorylation Tyr90 SETTVELySLAERCR 9606 10652356 t llicata Tyrosine 90 (tyr-90) in the regulatory domain of pkctheta was identified as the major phosphorylation site by lck. SIGNOR-74574 0.567 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 0.472 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 0.8 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 0.324 CDK9 protein P50750 UNIPROT H1-4 protein P10412 UNIPROT down-regulates activity phosphorylation Ser187 KPKKAPKsPAKAKAV 9606 28539972 t miannu These data provide further evidence that CDK9 phosphorylates H1.4-S187, and that the level of pS187-H1.4 at genes is directly related to the extent of co-enrichment of CDK9.|that enrichment of pS187-H1.4 at genes is positively related to their transcription. SIGNOR-279691 0.2 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 0.681 PPP2CA protein P67775 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-103162 0.647 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser270 SVRMLSGsKEKDRNL 9606 BTO:0000671 10908300 t gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. SIGNOR-79682 0.2 TGFB1 protein P01137 UNIPROT SHC1 protein P29353 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-242631 0.454 TNKS2 protein Q9H2K2 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000007 19759537 t Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-261248 0.451 ZMYM2 protein Q9UBW7 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity binding 9606 BTO:0000599 32439918 t miannu Here we have identified the zinc-finger proteins ZMYM2 and ZMYM4 as novel B-MYB binding proteins. B-MYB has been implicated in cell cycle progression at two steps, namely at the G1/S- and the G2/M-transition. ZMYM2 is required for the G1/S-transition in HepG2 cells. SIGNOR-269801 0.2 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser63 NVKVETQsDEENGRA 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 / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174832 0.29 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 15574335 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-131442 0.825 YWHAB protein P31946 UNIPROT SRPK2 protein P78362 UNIPROT down-regulates binding 9606 phosphorylation:Thr492 PSHDRSRtVSASSTG 19592491 t lperfetto 14-3-3 interacts with akt-phosphorylated srpk2 and blocks its nuclear translocation. kt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. SIGNOR-186767 0.33 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 0.2 PRKACG protein P22612 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 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-259404 0.2 FOXC1 protein Q12948 UNIPROT SOX4 protein Q06945 UNIPROT up-regulates quantity by expression transcriptional regulation 31650548 f lperfetto Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX15 SIGNOR-275917 0.319 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-98289 0.2 MED21 protein Q13503 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266678 0.814 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 0.753 CREM protein Q03060 UNIPROT IL2 protein P60568 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 12626549 t Luana In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production. SIGNOR-261576 0.481 RAC1 protein P63000 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248250 0.75 MKRN4P protein Q13434 UNIPROT MAP4K3 protein Q8IVH8 UNIPROT down-regulates quantity ubiquitination Lys650 PVAIPAHkLPDRILP 9606 34610951 t miannu MKRN4 ubiquitinated GLK at Lys650 residue.|Remarkably, MKRN4 overexpression induced GLK protein degradation in HEK293T cells and Jurkat T cells (figure 5A and B). SIGNOR-278658 0.2 JAK3 protein P52333 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Tyr415 ALGINSGySKRALML 9606 20176813 t miannu We identified three kinases capable of phosphorylating pld2 in vitro-epidermal growth factor receptor (egfr), jak3, and src (with jak3 reported for the first time in this study)-that phosphorylate an inhibitory, an activator, and an ambivalent (one that can yield either effect) site, respectively. Mass spectrometry analyses indicated the target of each of these kinases as y(296) for egfr, y(415) for jak3, and y(511) for src. SIGNOR-163858 0.407 SATB1 protein Q01826 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000725 23563689 f miannu Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc SIGNOR-224835 0.336 MTOR protein P42345 UNIPROT EIF4EBP3 protein O60516 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase. SIGNOR-122035 0.358 UNG protein P13051 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275711 0.7 GSC protein P56915 UNIPROT EVX1 protein P49640 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-254140 0.253 WNT8A protein Q9H1J5 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-131984 0.621 Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity binding 9606 BTO:0000427 9511957 t miannu  Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood.  SIGNOR-270351 0.2 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 0.8 SPI1 protein P17947 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12433372 f irozzo Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages. SIGNOR-256069 0.577 AKAP11 protein Q9UKA4 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates quantity binding 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-273741 0.425 UBE2N protein P61088 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000785 14713952 t lperfetto Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38. SIGNOR-121274 0.428 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 0.303 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr418 LSGEDDAyCTFPSRD 9534 BTO:0000298 8700888 t In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. SIGNOR-251340 0.631 SRC protein P12931 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr142 MELALGQyHRNGCIS 10116 BTO:0000132 21992875 t miannu We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.  SIGNOR-276386 0.258 JNJ-28312141 free base chemical CID:11676971 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258125 0.8 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 SIGNOR-C16 12105215 t llicata We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1 SIGNOR-90442 0.346 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000785 16847353 t lperfetto C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma SIGNOR-209593 0.627 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates phosphorylation Ser295 VIRPRRRsSCVSLGE 9606 10454575 t esanto 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-252583 0.687 IL1R1 protein P14778 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 9625767 t inferred from 70% of family members lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab SIGNOR-269883 0.379 GTF3C5 protein Q9Y5Q8 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-266184 0.913 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89272 0.394 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT up-regulates activity binding -1 8683730 t lperfetto Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production. SIGNOR-270548 0.422 TGFB1 protein P01137 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252282 0.7 DOCK6 protein Q96HP0 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 23462102 t lperfetto Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. SIGNOR-275670 0.528 AMG 900 chemical CID:24856041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189495 0.8 EDNRB protein P24530 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257321 0.435 LEPR protein P48357 UNIPROT AGRP protein O00253 UNIPROT down-regulates quantity 27154742 f lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production SIGNOR-253076 0.451 C1QBP protein Q07021 UNIPROT KRT1 protein P04264 UNIPROT up-regulates activity binding 9606 14691569 t Regulation of binding miannu Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored. SIGNOR-251881 0.373 Nitrendipine chemical CID:4507 PUBCHEM NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 t Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  SIGNOR-257767 0.8 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 0.459 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 0.2 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 SIGNOR-C13 15489227 t gcesareni Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-129943 0.439 SIAH1 protein Q8IUQ4 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 t lperfetto Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system SIGNOR-140612 0.676 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser857 ASPSRPEsPRPPFDL 9606 BTO:0000142 15287745 t lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. SIGNOR-127444 0.416 TRIM25 protein Q14258 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity ubiquitination Lys412 VWSAVTGkCLRTLVG 9606 BTO:0002181 31186535 t miannu This newly stabilized TRIM25 then directly ubiquitinates Lys412 of FBXW7α, a core subunit of the SKP1-Cullin-F-box (SCF) ubiquitin ligase complex involved in Myc ubiquitination, thereby stabilizing Myc.  SIGNOR-277457 0.264 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding 10090 BTO:0000011 26893351 t SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis. SIGNOR-256073 0.654 BRAF protein P15056 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 f These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. SIGNOR-259373 0.7 NANOG protein Q9H9S0 UNIPROT LAMB1 protein P07942 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254628 0.266 CHMP4B protein Q9H444 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265533 0.731 GRID2IP protein A4D2P6 UNIPROT GRID2 protein O43424 UNIPROT up-regulates quantity binding 9606 11826110 t miannu We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules. SIGNOR-264475 0.609 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 0.2 PTH1R protein Q03431 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 23151663 t gcesareni Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt. SIGNOR-199533 0.337 Gbeta proteinfamily SIGNOR-PF4 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 27846390 t inferred from 70% family members 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-269999 0.2 LRRK1 protein Q38SD2 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity phosphorylation Ser72 AGQERFQsLGVAFYR 9606 33459343 t miannu Overall, these data suggest that LRRK1 is able to phosphorylate endogenous Rab7A at Ser72. SIGNOR-278212 0.386 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 0.403 SP4 protein Q02446 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-225382 0.2 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity. SIGNOR-250295 0.834 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser477 ELIERKTsSLDPNDQ 9606 BTO:0001109 17157788 t lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. SIGNOR-264417 0.358 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CASP3 protein P42574 UNIPROT down-regulates activity 9606 BTO:0002882 11684015 f lperfetto BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation| SIGNOR-271704 0.2 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 0.475 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 0.406 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 0.262 SUV39H1 protein O43463 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 f lperfetto The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation SIGNOR-249601 0.404 VRK1 protein Q99986 UNIPROT SOX2 protein P48431 UNIPROT up-regulates activity phosphorylation 9606 27334688 t miannu VRK1, but not kinase-dead VRK1 (K179E), phosphorylated Sox2 (XREF_FIG). SIGNOR-279578 0.468 THRA protein P10827 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268550 0.2 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser558 AEQMANDsDDSISAA -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265896 0.2 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 0.819 NDUFS1 protein P28331 UNIPROT NADH-ubiquinone oxidoreductase-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-262175 0.858 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t gcesareni Mechanism of protein tyrosine phosphatase 1b-mediated inhibition of leptin signalling. Ptp1b plays a critical role in the down-regulation of activated-stat3 by dephosphorylating tyr705, that is the phosphorylation site of activation of stat3. SIGNOR-135211 0.552 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 0.2 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 0.913 PRKAA1 protein Q13131 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 t 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-265729 0.2 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates activity binding 9606 BTO:0000399 10706854 t Eotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases. SIGNOR-256091 0.936 HIPK2 protein Q9H2X6 UNIPROT AATF protein Q9NY61 UNIPROT down-regulates quantity phosphorylation 9606 25210797 t miannu HIPK2 phosphorylates Che-1.|Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation. SIGNOR-278942 0.346 BCL2L1 protein Q07817 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity binding 9606 9539746 t lperfetto Bcl2l1 associates with casp9 and apaf-1 in mammalian cells.Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation SIGNOR-56402 0.681 CDK1 protein P06493 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser484 SLIVPGKsPTRKKSG 9606 1406653 t lperfetto Two of the sites of phosphorylation by cyclic amp (camp)-dependent kinase were localized to serine residues 490 and 499, and one site of phosphorylation by p34cdc2 was localized to serine 484. SIGNOR-18735 0.445 ATF4 protein P18848 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260170 0.816 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT down-regulates activity phosphorylation Ser1050 AASLLRLsLYNNCIC 9606 BTO:0000984 11416140 t lperfetto Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription. SIGNOR-108569 0.309 PLK1 protein P53350 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Ser57 SQSSQDSsPVRNLQS 9606 18250300 t lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. SIGNOR-160751 0.503 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Thr1074 QRGSSGHtPPPSGPP 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259862 0.334 metyrapone chemical CHEBI:44241 ChEBI CYP11B2 protein P19099 UNIPROT down-regulates activity chemical inhibition -1 21129965 t Luana In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades. SIGNOR-257885 0.8 KAT8 protein Q9H7Z6 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267160 0.652 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQB2 protein P05538 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-253997 0.2 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190407 0.8 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 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-84053 0.704 PIK-294 chemical CID:24905149 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206202 0.8 TRIM13 protein O60858 UNIPROT AKT1 protein P31749 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-271852 0.353 959122-11-3 chemical CID:24768261 PUBCHEM DGAT1 protein O75907 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205695 0.8 IC-87114 chemical CHEBI:90686 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206190 0.8 PIN4 protein Q9Y237 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000567 12860119 f lperfetto Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs  SIGNOR-265754 0.7 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity phosphorylation Tyr153 LAYILSMePCGHCLI 9606 15657060 t Manara We show that ABL1 phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. ! Moreover, inhibition of ABL1 with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3. SIGNOR-260792 0.513 PRKCA protein P17252 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Thr475 TPLSSSNtIRRPRNY -1 1322130 t lperfetto The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme. SIGNOR-248844 0.439 PRKCG protein P05129 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-249249 0.293 MLKL protein Q8NB16 UNIPROT Necroptosis phenotype SIGNOR-PH174 SIGNOR up-regulates activity 9606 24316671 t gianni Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. SIGNOR-266431 0.7 FGF2 protein P09038 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 f lperfetto Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGFbeta-1. Meanwhile, blocking endogenous FGF signaling, using a virally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts SIGNOR-134785 0.471 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 t lperfetto Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-187975 0.773 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 0.565 TP53 protein P04637 UNIPROT GLS2 protein Q9UI32 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22307140 t Luana Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G SIGNOR-268041 0.631 neostigmine chemical CHEBI:7514 ChEBI 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-257758 0.8 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 0.911 CAMK4 protein Q16566 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t gcesareni Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-153940 0.708 ITSN1 protein Q15811 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 t lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth SIGNOR-260714 0.58 TRIM59 protein Q8IWR1 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity 9606 BTO:0000567; BTO:0002181 22588174 f Giorgia TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal SIGNOR-260374 0.259 ATG12 protein O94817 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 t lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). SIGNOR-226689 0.868 RNF146 protein Q9NTX7 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263339 0.262 TIMELESS protein Q9UNS1 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates activity binding 9534 23418588 t miannu We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. SIGNOR-268053 0.674 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 0.676 Gbeta proteinfamily SIGNOR-PF4 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-270057 0.2 (-)-anisomycin chemical CHEBI:338412 ChEBI p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates chemical activation 9606 Other t CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni SIGNOR-269916 0.8 DTL protein Q9NZJ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000007 24962565 t miannu TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner SIGNOR-272848 0.695 HRAS protein P01112 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity phosphorylation Ser192 PSTTGAAsPASSSAG 9606 25056917 f Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity SIGNOR-259945 0.356 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser392 QDAPIILsDSEEEEM 9606 19217413 t lperfetto Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay SIGNOR-184031 0.2 CUL9 protein Q8IWT3 UNIPROT FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 35469017 t miannu M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2. SIGNOR-276718 0.2 MKRN1 protein Q9UHC7 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 19536131 t miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21.  SIGNOR-271845 0.313 NEDD4 protein P46934 UNIPROT LYN protein P07948 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001931 10683340 t miannu These findings suggest that LMP2A recruits Nedd4-like ubiquitin-protein ligases and B-cell signal transduction molecules, resulting in the degradation of LMP2A and Lyn by a ubiquitin-dependent mechanism.  SIGNOR-272558 0.459 SELP protein P16109 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261860 0.408 cholesterol smallmolecule CHEBI:16113 ChEBI SOAT1 protein P35610 UNIPROT up-regulates activity chemical activation 9606 BTO:0000759 31848472 t miannu Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters SIGNOR-265159 0.8 TNK2 protein Q07912 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr365 AYQSRDYyNFPLALA 9606 25950519 t miannu Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain.|Mutation of these two sites in AR inhibited Ack1 induced AR transactivation and DNA binding as well as tumor growth. SIGNOR-278195 0.545 RAB23 protein Q9ULC3 UNIPROT GLI3 protein P10071 UNIPROT down-regulates 9606 16364285 f gcesareni Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization. SIGNOR-143160 0.579 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UBTF protein P17480 UNIPROT up-regulates activity phosphorylation Ser484 ERGKLPEsPKRAEEI 10090 BTO:0000944 10202152 t llicata We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro.  SIGNOR-250754 0.339 MAPK1 protein P28482 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 10090 BTO:0000782 16888006 t lperfetto ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition SIGNOR-148616 0.533 CDK4 protein P11802 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 SIGNOR-C18 18071316 t llicata This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4. SIGNOR-159849 0.409 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t gcesareni 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-236876 0.654 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 0.421 EFNA3 protein P52797 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t gcesareni Eph receptors are activated by their ligands, which are membrane-anchored molecules SIGNOR-52315 0.826 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248382 0.259 RAB5A protein P20339 UNIPROT PIK3R4 protein Q99570 UNIPROT up-regulates activity binding 10090 27411398 t lperfetto Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity SIGNOR-260708 0.422 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 0.726 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 0.28 TRIM28 protein Q13263 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 17900823 f inferred from family member miannu We previously reported that ZNF224, a novel Kr√ºppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. SIGNOR-270228 0.2 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8557118 t gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-249671 0.365 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252882 0.412 SCF-betaTRCP complex SIGNOR-C5 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11359933 t miannu Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCF(Fbw1a) consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed betaTrCP1) induces ubiquitination of Smad3.  SIGNOR-272944 0.443 INTS11 protein Q5TA45 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261462 0.2 MTMR2 protein Q13614 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269808 0.8 CCT129202 chemical CID:16202152 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190883 0.8 CASP5 protein P51878 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-256418 0.62 DOCK6 protein Q96HP0 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 23462102 t lperfetto Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. SIGNOR-275671 0.677 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 17158707 t lperfetto The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity SIGNOR-36466 0.2 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 0.585 NEDD9 protein Q14511 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 16184168 t miannu HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins. SIGNOR-262653 0.57 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 0.502 CMA1 protein P23946 UNIPROT EDN1 protein P05305 UNIPROT up-regulates activity cleavage Tyr83 TPEHVVPyGLGSPRS 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-256356 0.472 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB1 protein P01911 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 t 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-253977 0.283 CACNA2D3 protein Q8IZS8 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 27583705 t miannu Our findings showed that increased intracellular calcium (Ca2+ ) mediated by overexpression of CACNA2D3 induced mitochondrial-mediated apoptosis, upregulation of NLK (through the Wnt/Ca2+ pathway) and inhibition of the epithelial-to-mesenchymal transition. SIGNOR-266853 0.8 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 0.657 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser321 KCQRLFRsPSMPCSV 9606 20801879 t gcesareni Ser(321) is phosphorylated in mitosis by cdk1. The mitotic phosphorylation of ser(321) acts to maintain full activation of cdc25b by disrupting 14-3-3 binding to ser(323) and enhancing the dephosphorylation of ser(323) to block 14-3-3 binding to this site. SIGNOR-167641 0.829 CDK4 protein P11802 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176527 0.511 POLR1D protein P0DPB5 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266158 0.895 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr261 GLVTTLHyPAPKCNK -1 15735735 t miannu The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site. SIGNOR-276033 0.2 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 0.395 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). SIGNOR-70453 0.747 NEK6 protein Q9HC98 UNIPROT EML4 protein Q9HC35 UNIPROT up-regulates activity phosphorylation Ser144 QSPQIRAsPSPQPSS -1 31409757 t done miannu The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression. SIGNOR-273883 0.253 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 0.542 UPF2 protein Q9HAU5 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding -1 18066079 t miannu UPF2 and UPF3b increase UPF1 ATPase activity SIGNOR-265246 0.979 EP300 protein Q09472 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 t lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. SIGNOR-170273 0.668 PRKG2 protein Q13237 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser712 SDKRRPPsAELYSNA 9606 BTO:0000498 29935031 t miannu PKG II inhibited PDGFRβ activation in gastric cancer via phosphorylating Ser712 of this RTK. SIGNOR-277401 0.272 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity relocalization 9606 20704570 t lperfetto Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses SIGNOR-232107 0.389 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM8 protein O00222 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264073 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation -1 11287604 t inferred from 70% family members lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 SIGNOR-270109 0.2 GART protein P22102 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267315 0.8 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT down-regulates activity phosphorylation Ser537 REASRESsRDTSPVR 9534 BTO:0004055 19638411 t lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells SIGNOR-264826 0.515 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27141364 f irozzo EML4-ALK enhanced HIF-1α expression through increasing transcription and decreasing ubiquitination of HIF-1α. SIGNOR-259172 0.2 tyrosine smallmolecule CHEBI:18186 ChEBI tyramine smallmolecule CHEBI:15760 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬¨‚Ć SIGNOR-264175 0.8 PLAAT3 protein P53816 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates 9606 17374643 f miannu The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity. SIGNOR-153775 0.2 CALM3 protein P0DP25 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 BTO:0001853 24379783 t miannu Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-266339 0.565 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189984 0.8 NPY protein P01303 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t gcesareni Npy expression significantly increases whereas the gene expression of its receptors npy1r, npy2r, and npy5r initially decreases. SIGNOR-114746 0.74 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys608 LLAEEKSKPIPIMPA 9606 BTO:0000007 19638400 t Barakat Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. SIGNOR-274130 0.534 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 0.429 DUSP1 protein P28562 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 t gcesareni Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2. SIGNOR-46079 0.789 STK4 protein Q13043 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 t miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  SIGNOR-277920 0.2 TNF protein P01375 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 10485710 t gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k) SIGNOR-70625 0.296 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser33 LRRSQRKsGSELPSI -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276116 0.629 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249121 0.341 PRKACA protein P17612 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 t gcesareni Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation. SIGNOR-265344 0.2 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser373 RASSRASsRPRPDDL 9606 16474210 t lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. SIGNOR-144473 0.44 ibuprofen chemical CHEBI:5855 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-258325 0.8 TTK protein P33981 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity phosphorylation 18541701 t lperfetto Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2. SIGNOR-252036 0.713 UPF3B protein Q9BZI7 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding -1 18066079 t miannu UPF2 and UPF3b increase UPF1 ATPase activity SIGNOR-265247 0.957 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 0.294 EEF1A2 protein Q05639 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269524 0.8 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 0.481 DOK1 protein Q99704 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257680 0.297 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 11013247 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-82501 0.594 WICH complex SIGNOR-C449 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity 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-268829 0.412 DIO proteinfamily SIGNOR-PF83 SIGNOR iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† SIGNOR-267045 0.8 MINK1 protein Q8N4C8 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 t miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  SIGNOR-276336 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 t lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252794 0.461 MTOR protein P42345 UNIPROT ATG13 protein O75143 UNIPROT down-regulates phosphorylation 9606 19211837 t gcesareni Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2. SIGNOR-183965 0.651 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. SIGNOR-138920 0.341 GRIK1 protein P39086 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268272 0.8 ITGAM protein P11215 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 23994464 t apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. SIGNOR-255041 0.773 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates phosphorylation Ser623 KGEKRASsPFRRVRE 9606 12167624 t gcesareni Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically. SIGNOR-91186 0.307 CREBBP protein Q92793 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 f lperfetto In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE SIGNOR-254093 0.2 Pr3-ANCA complex SIGNOR-C475 SIGNOR Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000133 2161532 f lperfetto ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. SIGNOR-270584 0.7 CTNNB1 protein P35222 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0004086 17420453 f Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. SIGNOR-256534 0.7 ATG101 protein Q9BSB4 UNIPROT ATG13 protein O75143 UNIPROT up-regulates binding 9606 19597335 t gcesareni Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1 SIGNOR-186989 0.959 PH 797804 chemical CHEBI:82715 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206079 0.8 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation 9606 18243099 t amattioni Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment SIGNOR-160604 0.461 CSNK1D protein P48730 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates activity phosphorylation 9606 22123863 t miannu We further show that casein kinase 1\u03b4 binds and phosphorylates EB1 and promotes microtubule growth. SIGNOR-279165 0.505 CASP2 protein P42575 UNIPROT Caspase 2 complex complex SIGNOR-C227 SIGNOR form complex binding cleavage:Asp347 SPGCEESdAGKEKLP 21828056 t lperfetto Like other caspases, caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit (p19) and the small subunit (p12). This p19/p12 dimer self-associates to form the active caspase-2 SIGNOR-256389 0.2 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12471034 t gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). SIGNOR-96250 0.967 SRC protein P12931 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr220 RHSVVVPyEPPEVGS 9606 BTO:0002181 25071020 t miannu We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation by enhancing Herc5 binding. SIGNOR-276669 0.524 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 0.251 CEBPA protein P49715 UNIPROT Mast-Cell_diff phenotype SIGNOR-PH117 SIGNOR down-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-259967 0.7 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120072 0.789 MAPK1 protein P28482 UNIPROT RAI14 protein Q9P0K7 UNIPROT unknown phosphorylation Thr249 SQDADLKtPTKPKQH 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262760 0.266 POU5F1 protein Q01860 UNIPROT ZFP42 protein Q96MM3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254944 0.464 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 0.291 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 SIGNOR-C83 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-100881 0.767 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 9606 21873209 t lperfetto 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-209702 0.95 MEIS1 protein O00470 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. SIGNOR-255860 0.7 CYP24A1 protein Q07973 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI down-regulates quantity chemical modification 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270572 0.8 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.748 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Ser197 AAQRCTIsYRAPELF -1 18184589 t Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. SIGNOR-260804 0.2 GATA3 protein P23771 UNIPROT FOXC2 protein Q99958 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 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-254089 0.331 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 0.2 FOXS1 protein O43638 UNIPROT FASLG protein P48023 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 BTO:0004577 18288644 t Luana As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells SIGNOR-261612 0.2 MYC protein P01106 UNIPROT HLA-A protein P04439 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254603 0.268 TRIM9 protein Q9C026 UNIPROT VASP protein P50552 UNIPROT down-regulates quantity ubiquitination 9606 26702829 t miannu TRIM9 ubiquitinates VASP but not Mena or EVL.|Thus TRIM9 negatively regulates VASP localization to filopodia tips, whereas netrin promotes VASP tip localization. SIGNOR-278580 0.345 CDC7 protein O00311 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 t gcesareni We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1. SIGNOR-200397 0.432 VDAC1 protein P21796 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10365962 f lperfetto Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis. SIGNOR-249615 0.7 BAG1 protein Q99933 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity binding 9606 BTO:0000661 7834747 t lperfetto Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity| SIGNOR-254118 0.415 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 0.2 mTORC1 complex SIGNOR-C3 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256172 0.342 CSNK2A1 protein P68400 UNIPROT TCOF1 protein Q13428 UNIPROT up-regulates activity phosphorylation Thr210 TSSSSDEtDVEGKPS 9606 BTO:0000567 25064736 t lperfetto Phosphorylated Thr 210 in Treacle is the major interaction site for NBS1|A purified GST fragment of this region was efficiently phosphorylated by CK2 in vitro (Supplementary Fig. 4; T-2) and this fragment pulled down the MRN complex from Hela nuclear extracts only when previously phosphorylated by CK2 SIGNOR-265086 0.305 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 0.2 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 0.428 POLR2F protein P61218 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266148 0.901 MC5R protein P33032 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256941 0.292 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 0.666 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR OPTN protein Q96CV9 UNIPROT up-regulates activity polyubiquitination Lys501 LQLAVLLkENDAFED 9606 BTO:0000567 32014991 t miannu DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut. SIGNOR-272209 0.2 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000938 17591690 t llicata We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active SIGNOR-156426 0.732 GALP protein Q9UBC7 UNIPROT GALR2 protein O43603 UNIPROT up-regulates binding 9606 10601261 t gcesareni Galp is therefore an endogenous ligand that preferentially binds the galr2 receptor SIGNOR-73143 0.43 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000938 24431436 t miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204357 0.813 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 0.48 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 0.2 GRK2 protein P25098 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10852916 t llicata We found that grk-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and pld2. These findings suggest that gpcrs may be able to indirectly stimulate pld2 activity via their ability to regulate grk-promoted phosphorylation of synuclein. SIGNOR-78333 0.2 trichostatin A chemical CHEBI:46024 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-258012 0.8 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 25910399 f Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. SIGNOR-257599 0.7 A11/b1 integrin complex SIGNOR-C168 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257710 0.57 SYK protein P43405 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 11226282 t lperfetto We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. SIGNOR-247586 0.589 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 2846551 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-23753 0.2 PSMA1 protein P25786 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263363 0.861 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 0.2 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001412 11283671 t irozzo AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo. SIGNOR-255700 0.2 tyrphostin B42 chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity 9606 11368440 t gcesareni The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel SIGNOR-238293 0.8 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1265 FPMTPTTyKGSVDNQ 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104080 0.2 PD-153035 hydrochloride chemical CHEBI:91075 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205716 0.8 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Ser385 RYSDTTDsDPENEPF 9606 BTO:0001938 15987703 t lperfetto We provide evidence suggesting that LKB1 phosphorylates PTEN at residue S385 in combination either with S380, T382 or T383 SIGNOR-247446 0.604 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH12 protein P55289 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-265830 0.8 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 0.447 BDKRB2 protein P30411 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257399 0.2 MBOAT7 protein Q96N66 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267247 0.8 LCK protein P06239 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation 9606 10799545 t Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates. SIGNOR-251373 0.6 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75922 0.622 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 0.729 BTK protein Q06187 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated SIGNOR-98086 0.496 NDUFV2 protein P19404 UNIPROT NADH-ubiquinone oxidoreductase-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 0.86 HOXC10 protein Q9NYD6 UNIPROT LAMB2 protein P55268 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10835276 t Luana The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells. SIGNOR-261645 0.2 SNRPG protein P62308 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-270659 0.729 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 0.8 MAPK14 protein Q16539 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 12589053 f fspada Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma.  SIGNOR-210090 0.395 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr642 RGVHHIDyYKKTSNG 9606 BTO:0001130 18670643 t lperfetto Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4. SIGNOR-179776 0.2 TRAF6 protein Q9Y4K3 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity 9606 BTO:0000007 16371247 f The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6. SIGNOR-252254 0.417 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser518 PSTSKAVsPPHLDGP 9606 BTO:0000551 16873060 t gcesareni Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517. SIGNOR-148306 0.342 LMNA protein P02545 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 23401537 f lperfetto Mammalian lamin meshworks consist of two types of lamin proteins, A type and B type, and it has been reported that nuclear blebs are enriched in A-type lamins. SIGNOR-83706 0.7 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191481 0.8 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 0.323 PEX1 protein O43933 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis. SIGNOR-253616 0.7 NFY complex SIGNOR-C1 SIGNOR CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 BTO:0000887;BTO:0001103 10362252 f lperfetto In conclusion, our data demonstrate that nf-y is required for cyclin b1 promoter activity. SIGNOR-235834 0.356 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 SIGNOR-C3 20516213 t fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-165795 0.712 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation 9606 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-270046 0.2 CD38 protein P28907 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264246 0.8 SEC24D protein O94855 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265291 0.691 ATR protein Q13535 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation Ser67 DERVKEPsQDTVATE 31938050 t lperfetto Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h. SIGNOR-275850 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 t lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 0.8 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. SIGNOR-66730 0.355 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR S100A6 protein P06703 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12859951 f miannu NF-kappaB transcription factor contributes to the activation of S100A6 gene expression in response to TNFalpha in HepG2 cells. SIGNOR-254803 0.2 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCG protein P05129 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190356 0.8 PRC1 protein O43663 UNIPROT KIF23 protein Q02241 UNIPROT up-regulates activity binding 9606 15297875 t miannu These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins. SIGNOR-265989 0.572 HBA1 protein P69905 UNIPROT CYP2E1 protein P05181 UNIPROT up-regulates activity 9606 BTO:0000575 19325051 f Regulation miannu Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. SIGNOR-251765 0.2 EGFR protein P00533 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates phosphorylation Tyr66 LHQEDNDyINASLIK 9606 9355745 t llicata After binding to egfr, ptp1b becomes tyrosine-phosphorylated at tyr-66 phosphorylation of ptp1b by egfr enhances its catalytic activity SIGNOR-52950 0.76 MID2 protein Q9UJV3 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 35266954 t miannu The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity. SIGNOR-278763 0.2 HDAC1 protein Q13547 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-255179 0.384 Dihydromorphine chemical CHEBI:4575 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258788 0.8 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 0.748 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 16362042 t gcesareni Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. SIGNOR-143109 0.905 diazepam chemical CHEBI:49575 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 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-263796 0.8 PRKACA protein P17612 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Thr369 DLINKKItPPFNPNV -1 11096081 t miannu In this publication, we demonstrate that cAMP can activate Sgk and that this effect is mediated by PKA, which directly phosphorylates Thr369 in Sgk.  SIGNOR-275972 0.297 YWHAQ protein P27348 UNIPROT CDC25C protein P30307 UNIPROT down-regulates relocalization 9606 20068082 t gcesareni Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins. SIGNOR-163237 0.575 SRC protein P12931 UNIPROT HK1 protein P19367 UNIPROT down-regulates activity phosphorylation Tyr732 YDRLVDEySLNAGKQ 9606 28054552 t miannu Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its K m and increases its V max by disrupting its dimer formation.|Mechanistically, c-Src-mediated Y732 phosphorylation disrupts HK1 dimer formation, alters its enzyme kinetics and eventually enhances enzymatic activity ( ). SIGNOR-278209 0.492 TBX21 protein Q9UL17 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000782 20154735 f azuccotti Similarly, an increase in IL-10 expression was observed in mice deficient for the TH1 cell-specific transcription factor T-bet (also known as TBX21) that were infected with M.tuberculosis, suggesting that T-bet might have a role in the negative regulation of IL-10 expression by TH1 cells SIGNOR-254524 0.446 MMP3 protein P08254 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-253320 0.67 GSK3B protein P49841 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity phosphorylation Ser166 GAEDTASsQLGFGVL 9606 29328365 t miannu Based on these observations, we hypothesized that the IR induced GSK3beta nuclear translocation may activate 53BP1 via phosphorylation at the S/T-Q motif.|Importantly, our in vivo and in vitro data clearly indicated that GSK3\u03b2 induced the phosphorylation of 53BP1 at the Ser166 site. SIGNOR-278226 0.283 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 0.7 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 0.435 HARS1 protein P12081 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270803 0.8 ZSTK-474 chemical CHEBI:90545 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252646 0.8 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12270934 f lperfetto We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process. SIGNOR-244773 0.2 MAVS protein Q7Z434 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260144 0.832 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 0.2 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258993 0.75 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 0.398 NOX3 protein Q9HBY0 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264722 0.8 CASP3 protein P42574 UNIPROT MYL3 protein P08590 UNIPROT down-regulates quantity by destabilization cleavage Glu135 GTYEDFVeGLRVFDK 9986 BTO:0003324 12186978 t lperfetto By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE(135)G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance. SIGNOR-270593 0.377 PRKCA protein P17252 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by stabilization phosphorylation Ser144 TLPSDKLsKIQTLKL 9606 BTO:0002181 30733340 t miannu Because most of these sites were predicted to be phosphorylated by protein kinase C (PKC), we overexpressed PKCα in several cell lines and found that it phosphorylates Twist1 on Ser-144. we observed that PKCα-mediated Twist1 phosphorylation at Ser-144 inhibits Twist1 ubiquitination and consequently stabilizes it. SIGNOR-277429 0.2 PPP1CA protein P62136 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR down-regulates activity dephosphorylation 9606 14751588 t miannu Dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa (DARPP-32) is a key element of dopamine/D1/DARPP-32/protein phosphatase-1 (PP-1) signaling cascades of mammalian brain. Phosphorylation of AMPA receptors due to DARPP-32/PP1 signaling cascade increases AMPA channel activity and currents SIGNOR-265060 0.513 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194952 0.8 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 0.422 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser149 RRGASDLsSEEGWRL -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-250950 0.325 CBS protein P35520 UNIPROT L-serine zwitterion smallmolecule CHEBI:33384 ChEBI down-regulates quantity chemical modification 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275829 0.8 DTX4 protein Q9Y2E6 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 10531053 t gcesareni Nlrp4 negatively regulates type i interferon signaling by targeting the kinase tbk1 for degradation via the ubiquitin ligase dtx4 SIGNOR-71565 0.584 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-128264 0.418 LPAR2 protein Q9HBW0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257169 0.469 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 0.2 EGFR protein P00533 UNIPROT FUS protein P35637 UNIPROT up-regulates activity phosphorylation 9606 32678881 t miannu Thus, EGFR appears to mediate FUS nuclear translocation by phosphorylating Y6 and Y296 in FUS. SIGNOR-279168 0.259 EGFR protein P00533 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation 9606 30573522 t miannu EGFR and MET heterodimer interacts with and phosphorylates PARP1. SIGNOR-279169 0.394 MMP2 protein P08253 UNIPROT PZP protein P20742 UNIPROT down-regulates quantity by destabilization cleavage Thr718 PYVPQLGtYNVIPLN -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-261796 0.329 SNAI1 protein O95863 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000599 27239445 f Marta Tosoni We also observed that SNAI1 expression was correlated with distal metastasis, incomplete tumor capsule formation, and histological differentiation in hepatocellular carcinoma (HCC). SIGNOR-278098 0.7 MYCN protein P04198 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 f miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. SIGNOR-254214 0.3 FBXO22 protein Q8NEZ5 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 31138683 t lperfetto SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis|we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. SIGNOR-273440 0.2 DNAJC3 protein Q13217 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 t gcesareni The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK SIGNOR-246207 0.635 EDN1 protein P05305 UNIPROT EDNRA protein P25101 UNIPROT up-regulates binding 9606 16597412 t gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145759 0.881 Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260237 0.2 HOXB3 protein P14651 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 t Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively SIGNOR-261635 0.2 BDNF protein P23560 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32603820 f miannu BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain SIGNOR-265063 0.7 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity phosphorylation Ser99 KDGVADVsIEDSVIS 4932 24647101 t ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes. SIGNOR-262795 0.376 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 19151762 f lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 SIGNOR-242605 0.7 IRF3 protein Q14653 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 t lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation SIGNOR-251721 0.406 HDAC1 protein Q13547 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255175 0.264 CREB1 protein P16220 UNIPROT PLAT protein P00750 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001282 8647095 f lperfetto We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells. SIGNOR-253732 0.264 PRKCA protein P17252 UNIPROT ITPKB protein P27987 UNIPROT down-regulates activity -1 9374536 t lperfetto However, when assayed in the presence of calcium/calmodulin, the activity of the B isoform was decreased following phosphorylation by either protein kinase. SIGNOR-248990 0.359 INS protein P01308 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity 10116 15069075 f lperfetto The mechanism by which the phosphorylation of ser307 or ser318 inhibits irs-1 tyrosine phosphorylation is not known. Prolonged insulin-stimulation inhibits irs-1 binding to the phosphorylated npey motif in the juxta-membrane region of the irbeta -subunit. SIGNOR-236625 0.68 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC10 protein Q969S8 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-202108 0.8 PPP2CA protein P67775 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 24726876 t miannu RACK1 Negatively Regulates the Type I IFN pathway. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260944 0.314 ACTN1 protein P12814 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 27871158 t lperfetto Actin exists in polymer where filamin and α-actinin act as cross-linkers with approximately 1:10 ratios SIGNOR-261852 0.7 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr983 AAPPAPPtPPPPTLP -1 19448668 t miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. SIGNOR-262882 0.379 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 BTO:0000150;BTO:0000551 22139079 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-195157 0.2 SOX4 protein Q06945 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 f miannu These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα. SIGNOR-260133 0.7 CDK13 protein Q14004 UNIPROT 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-273057 0.541 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser714 ESSTNSSsQDYSTSQ 31938050 t lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. SIGNOR-275853 0.311 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys51 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272706 0.355 GSK3B protein P49841 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser62 EPDSGSHsRQSSTDS 9606 BTO:0002181 22692215 t miannu GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3  phosphorylation, whereas the Ser-66 is not (Fig. 4D). SIGNOR-277647 0.2 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Thr239 VPEMPGEtPPLSPID 9606 BTO:0000007 16023596 t lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance SIGNOR-236717 0.712 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr273 TTWTGSRtAPYTPNL 10090 BTO:0000944 25373906 t miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  SIGNOR-276440 0.398 CH5132799 chemical CID:49784945 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190946 0.8 MAPKAPK2 protein P49137 UNIPROT TSC2 protein P49815 UNIPROT unknown phosphorylation Ser1254 TALYKSLsVPAASTA 9606 12582162 t llicata Both in vitro and in vivo experiments demonstrate that the p38-activated kinase mk2 (also known as mapkapk2) is directly responsible for the phosphorylation of ser(1210). SIGNOR-98201 0.659 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser108 DVEELTAsQREAAER 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187388 0.962 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 0.753 USP37 protein Q86T82 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 21596315 t lperfetto USP37 Binds, Deubiquitinates, and Stabilizes Cyclin A SIGNOR-265052 0.581 COPS3 protein Q9UNS2 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270769 0.918 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser9 EEPQSDPsVEPPLSQ 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-115348 0.843 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 0.843 C5 protein P01031 UNIPROT C5AR1 protein P21730 UNIPROT up-regulates activity binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 1847994 t complement C5a (anaphylatoxin) fragment: PRO_0000005988 lperfetto The chemotactic receptor for human C5a anaphylatoxin|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells. SIGNOR-263457 0.757 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 0.76 FANCG protein O15287 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263254 0.737 MT-ND4L protein P03901 UNIPROT NADH-ubiquinone oxidoreductase-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-262147 0.692 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 0.2 SLIT1 protein O75093 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding 9606 16226035 t gcesareni Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit. SIGNOR-141111 0.897 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 0.502 SEMA3B protein Q13214 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261812 0.652 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138953 0.615 NF1 protein P21359 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-267847 0.398 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 0.2 TNF protein P01375 UNIPROT REL protein Q04864 UNIPROT up-regulates 9606 BTO:0000782 10823840 f miannu C-rel emerges as the main nf-kb family member stimulated by tnf_ in the context of physiologic activation of resting t cells. SIGNOR-77547 0.413 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 0.2 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 0.438 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 0.917 C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263481 0.558 ATF2 protein P15336 UNIPROT POLB protein P06746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001025 10518804 f miannu We identified the heterodimeric transcription factor ATF2/CREB as constitutively binding to the essential cAMP response element (CRE) site within the Ca2+-regulated DNA polymerase beta promoter and contributing to the activation of this promoter. SIGNOR-253744 0.2 HEXIM1 protein O94992 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 9606 18371977 t miannu Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. The mislocalization of HEXIM1 and the increased P-TEFb-dependent transcription caused by NPMc+ suggests that the misregulated activity of PTEFb may contribute to the tumorigenesis of NPMc+ AML. SIGNOR-260135 0.719 ANKRD11 protein Q6UB99 UNIPROT GAP43 protein P17677 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-266736 0.2 TNF protein P01375 UNIPROT JAG2 protein Q9Y219 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-253608 0.318 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 0.911 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 0.2 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 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-268589 0.25 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 0.7 PIK3CD protein O00329 UNIPROT PIK3CD protein O00329 UNIPROT down-regulates phosphorylation Ser1039 NWLAHNVsKDNRQ 9606 10064595 t gcesareni Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity. SIGNOR-65186 0.2 NUP155 protein O75694 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262082 0.75 BRCA1 protein P38398 UNIPROT TOP1 protein P11387 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002201 28415827 t miannu Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. Taken together, we conclude that BRCA1 is the E3 ligase for topoI, and the rate of topoI proteasomal degradation determines CPT response. SIGNOR-277353 0.463 TBK1 protein Q9UHD2 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity phosphorylation Thr189 TAKKNGGtLYYMAPE 9606 30146158 t miannu Our data clearly indicate that TBK1 can directly phosphorylate RIPK1 at T189.|TBK1 inhibits RIPK1 by direct phosphorylation. SIGNOR-279388 0.373 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 0.7 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000552 9736735 t lperfetto Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins|These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation. SIGNOR-267556 0.681 BTF3 protein P20290 UNIPROT RRAS2 protein P62070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17312387 f miannu 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. SIGNOR-253766 0.259 ULK2 protein Q8IYT8 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser115 ANAILGVsLAVCKAG 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-274038 0.2 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 0.2 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Ser234 MEDGTVQsSVAVGTP 9534 BTO:0000298 11283256 t miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). SIGNOR-275974 0.2 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 0.2 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity phosphorylation Ser349 QNWEEADsMKSSVES 9606 26928339 t miannu  CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.  SIGNOR-277212 0.307 LYL1 protein P12980 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 f miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. SIGNOR-198276 0.2 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 16301830 f VEGF as a key mediator of angiogenesis in cancer. SIGNOR-256597 0.7 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 0.345 MTNR1A protein P48039 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256706 0.476 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 0.805 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264442 0.2 NDUFC2 protein O95298 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262174 0.811 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 0.2 ARID1A protein O14497 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-270743 0.759 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 0.362 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b2-d) receptor complex SIGNOR-C328 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-264928 0.8 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity phosphorylation Ser1700 VNSDRRDsLQQTNTT -1 19074150 t miannu We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry. SIGNOR-263108 0.396 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1A protein P37288 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257461 0.8 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0001109 36882522 t lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. SIGNOR-273114 0.2 PPP3CA protein Q08209 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-248686 0.629 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 0.391 paliperidone chemical CHEBI:82978 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258563 0.8 CABIN1 protein Q9Y6J0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates 9606 17172641 f gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. SIGNOR-151205 0.669 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 0.668 OSI-420 chemical CID:18924996 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195248 0.8 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 0.432 TXK protein P42681 UNIPROT TXK protein P42681 UNIPROT up-regulates phosphorylation Tyr91 KIQVKALyDFLPREP 9606 12081135 t lperfetto Evidence of autophosphorylation in txk: y91 is an autophosphorylation site. the results suggest that phosphorylated txk is an active form to promote ifn-gamma synthesis SIGNOR-89844 0.2 NFIB protein O00712 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-268897 0.282 DYRK1A protein Q13627 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 22110360 t miannu Regarding to the functional role of Dyrk1A, active Dyrk1A phosphorylates the transcription factor cAMP response element -binding protein (CREB), which subsequently leads to the stimulation of cAMP response element-mediated gene transcription during neuronal differentiation ( ). SIGNOR-279989 0.487 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation Tyr1034 AIETDKEyYTVKDDR -1 12559972 t Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD) SIGNOR-251363 0.536 NARS2 protein Q96I59 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270463 0.8 SDHC protein Q99643 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 t lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites SIGNOR-262186 0.955 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT up-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ 8355 BTO:0001175 18803695 t miannu Recently, we have defined sites of phosphorylation by cAMP-dependent protein kinase (PKA) in the amino termini of both GRK1 and GRK7 in vitro. To determine the conditions under which GRK7 is phosphorylated in vivo, we have generated an antibody that recognizes GRK7 phosphorylated on Ser36, the PKA phosphorylation site. Using this phospho-specific antibody, we have shown that GRK7 is phosphorylated in vivo and is located in the cone inner and outer segments of mammalian, amphibian and fish retinas. The conservation of phosphorylation at Ser36 in GRK7 in these different species (which span a 400 million-year evolutionary period), and its light-dependent regulation, indicates that phosphorylation plays an important role in the function of GRK7 SIGNOR-263152 0.2 WWC1 protein Q8IX03 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity 9606 BTO:0000007 20159598 f Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. SIGNOR-269951 0.442 CASP3 protein P42574 UNIPROT DFFB protein O76075 UNIPROT up-regulates cleavage 9606 9108473 t gcesareni Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation SIGNOR-47419 0.684 Laminin-5 complex SIGNOR-C184 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 8832392 t lperfetto The initial adhesion of PA-JEB and normal keratinocytes to laminin-1 and laminin-5, both ligands for alpha 6 beta 1 and alpha 6 beta 4, was similar. SIGNOR-253253 0.598 HTRA2 protein O43464 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 11583623 t gcesareni Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo. SIGNOR-110834 0.709 TRRAP protein Q9Y4A5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269288 0.743 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1139 TCSPQPEyVNQPDVR -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251127 0.2 HOXB4 protein P17483 UNIPROT IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12489992 t Luana These data showed that Hox genes selectively activate the transcription of theIGFBP-1 SIGNOR-261636 0.2 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 t lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. SIGNOR-50891 0.639 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257044 0.385 p38 proteinfamily SIGNOR-PF16 SIGNOR DROSHA protein Q9NRR4 UNIPROT down-regulates activity phosphorylation Ser300 RHRDNRRsPSLERSY 9606 BTO:0000007 25699712 t lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  SIGNOR-264847 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation -1 9525907 t inferred from 70% family members miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-270058 0.2 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3. SIGNOR-248427 0.552 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR2 protein P30518 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257463 0.8 NR5A2 protein O00482 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-254873 0.363 THRA protein P10827 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 15650024 t inferred from 70% of family members gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-269851 0.432 HRH1 protein P35367 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-256921 0.2 verteporfin chemical CHEBI:32293 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0005079 27073720 f Verteporfin inhibits cell proliferation SIGNOR-278127 0.7 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 0.492 AKT2 protein P31751 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000150 12697749 t lperfetto Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity SIGNOR-100588 0.646 EPHA3 protein P29320 UNIPROT UXS1 protein Q8NBZ7 UNIPROT up-regulates activity phosphorylation 9606 25505462 t miannu However, it is possible that etk is a principal activator of Ugd.|The phosphorylation of the Ugd protein (a UDP-glucose dehydrogenase) by Etk increases Ugd dehydrogenase activity. SIGNOR-280006 0.2 CSNK2A1 protein P68400 UNIPROT SERINC3 protein Q13530 UNIPROT up-regulates activity phosphorylation Ser380 ILGDTTTsGASDEED -1 30135209 t miannu The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro. SIGNOR-273631 0.2 DNAAF10 protein Q96MX6 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270921 0.2 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser455 HFGSTSSsPPISPAS 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251244 0.397 NDN protein Q99608 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates 9606 24392140 f lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253383 0.278 STK38 protein Q15208 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 BTO:0000007 21262772 t no lperfetto More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. | SIGNOR-272961 0.2 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272713 0.747 (-)-anisomycin chemical CHEBI:338412 ChEBI FOSB protein P53539 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189629 0.8 PCSK7 protein Q16549 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation 9606 12435397 t gcesareni In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site SIGNOR-95622 0.2 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192892 0.8 CSNK2A2 protein P19784 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 23374587 t The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set SIGNOR-200802 0.259 NOD2 protein Q9HC29 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity binding 9606 17355968 t miannu The function of NOD2 could be to recruit RICK at the plasma membrane to form an active complex able to activate part of the NF-κB pathway. NOD2 induces a membrane recruitment of RICK that is dependent on a CARD-CARD interaction. SIGNOR-252402 0.765 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19162178 t gcesareni The hgf-induced wave2 transport, lamellipodia formation, stathmin/op18 phosphorylation at ser38 and binding to kinesin-wave2 complex, but not stathmin/op18 phosphorylation at ser25 and microtubule growth, were abrogated by pak1 inhibitor ipa-3 SIGNOR-183503 0.374 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity phosphorylation Tyr567 IRVDTPHyPRWITKE -1 11812791 t Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro SIGNOR-251407 0.557 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser14 PFSFGTLsSWELEAW 9606 BTO:0000567 12876286 t llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites SIGNOR-250850 0.344 CUDC-101 chemical CID:24756910 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262257 0.8 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr387 LMRTLCGtPTYLAPE 9606 BTO:0000007 11901158 t gcesareni Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387 SIGNOR-116131 0.2 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR2B protein P31994 UNIPROT up-regulates activity 9606 BTO:0000801 25475856 f lperfetto Low affinity-activating Fcgamma receptors (FcgammaRs) that bind immune complexes are controlled by a single inhibitory receptor, FcgammaRIIb (CD32b). SIGNOR-249522 0.7 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-96696 0.413 BCR protein P11274 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Thr232 LTLWTSDtQGDEAEA -1 16045749 t llicata We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233 SIGNOR-250595 0.331 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 0.79 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA -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-251292 0.654 FUBP1 protein Q96AE4 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30500954 f irozzo Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. SIGNOR-259132 0.2 MTHFR protein P42898 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 24769206 f miannu MTHFR promotes heterochromatin maintenance at the centromeric region. SIGNOR-263889 0.7 OGT protein O15294 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267158 0.557 DOCK10 protein Q96BY6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260549 0.522 PPP2R1A protein P30153 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-243427 0.924 PRKACA protein P17612 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a. SIGNOR-83221 0.372 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 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-263812 0.8 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.758 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 19647514 t lperfetto Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation SIGNOR-187383 0.2 NR3C1 protein P04150 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 10090 BTO:0000944 11742987 f inferred from 70% of family members gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. SIGNOR-269920 0.634 JAK2 protein O60674 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation 9606 9575217 t gcesareni Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-56894 0.865 SPAG9 protein O60271 UNIPROT ABL1 protein P00519 UNIPROT unknown binding 9606 BTO:0000222 SIGNOR-C21 19470755 t lperfetto We report that abl associates with both cdo and jlp during myoblast differentiation SIGNOR-185765 0.528 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 0.7 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 0.708 IKBKE protein Q14164 UNIPROT CDK2AP1 protein O14519 UNIPROT unknown phosphorylation Ser46 LSDYGPPsLGYTQGT -1 22427660 t lperfetto CDK2AP1 is phosphorylated at a conserved Ser-46 site in the N-terminal "intrinsically disordered" region by IkappaB kinase epsilon. SIGNOR-264780 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 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-270387 0.8 DMTF1 protein Q9Y222 UNIPROT DSPP protein Q9NZW4 UNIPROT up-regulates quantity by expression transcriptional regulation 23349460 t lperfetto In addition, our in vitro analyses showed that DMP1 and its 57-kDa C-terminal fragment significantly up-regulated the Dspp promoter activities in a mesenchymal cell line. SIGNOR-271685 0.2 PRKCG protein P05129 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-249196 0.359 NFIX protein Q14938 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268886 0.2 TRIB3 protein Q96RU7 UNIPROT ACACB protein O00763 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271601 0.258 CIITA protein P33076 UNIPROT HLA-DQB1 protein P01920 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11332992 f The class II transactivator (CIITA) regulates expression of the classical and non-classical MHC class II genes, HLA-DR, -DP, -DQ and -DM, SIGNOR-254017 0.517 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19254573 f fspada Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression. SIGNOR-184277 0.392 CFAP53 protein Q96M91 UNIPROT ODAD4 protein Q96NG3 UNIPROT up-regulates activity binding 10090 BTO:0000379 33347437 t miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). SIGNOR-265543 0.2 GNAS protein Q5JWF2 UNIPROT RACK1 protein P63244 UNIPROT down-regulates activity binding 9606 BTO:0000972 34657150 t Marta Tosoni The results showed that RACK1 severed as an oncogene to enhance the proliferation capacity of liver cancer cell lines, meanwhile, downregulated GNA14 expression in Huh7 cell lines reversed the effects of RACK1 on cell proliferation SIGNOR-278048 0.2 RACK1 protein P63244 UNIPROT PKC proteinfamily SIGNOR-PF53 SIGNOR up-regulates activity binding 6239 BTO:0005677 25280016 t Marta Tosoni The scaffolding protein RACK1 recruits and activates PKC in the cytoplasm SIGNOR-278067 0.2 NFIB protein O00712 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268899 0.249 MCM4 protein P33991 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-261674 0.777 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 0.753 DAXX protein Q9UER7 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 BTO:0000584 26428317 f Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors SIGNOR-256596 0.7 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates phosphorylation Tyr153 RGNADLAyILSMEPC 9606 15657060 t gcesareni C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9. SIGNOR-133260 0.513 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates activity sumoylation 9606 BTO:0000007 16061479 t miannu Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP SIGNOR-225481 0.331 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 0.7 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 0.7 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250802 0.364 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr410 GVVDSGVyAVPPPAE 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98569 0.256 sirolimus chemical CHEBI:9168 ChEBI AKT1 protein P31749 UNIPROT up-regulates 9606 16452206 f gcesareni We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001. SIGNOR-252643 0.8 PIM1 protein P11309 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation Thr210 YDGERKKtLCGTPNY 9606 24771642 t miannuccelli This data strongly indicates that Pim1 phosphorylates PLK1 at threonine 210, a site previously reported to be phosphorylated by aurora A kinase during mitosis. SIGNOR-279749 0.294 ALDOA protein P04075 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266487 0.8 AT-406 chemical CID:25022340 PUBCHEM BIRC3 protein Q13489 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189957 0.8 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189942 0.8 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser642 NACTLTTsPRLPVF 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249444 0.632 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269621 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD83 protein Q01151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 f miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. SIGNOR-254781 0.259 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT up-regulates activity phosphorylation Ser300 RHRDNRRsPSLERSY -1 25699712 t lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  SIGNOR-264845 0.278 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 0.8 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 12519765 t lperfetto Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm SIGNOR-253260 0.2 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 0.2 CCNF protein P41002 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27653696 t miannu We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. SIGNOR-266363 0.538 CAMK4 protein Q16566 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 32531122 t miannu CAMK4 phosphorylates GSK3\u03b2 at serine 9, which leads to its inactivation. xref Accordingly, we examined the levels of phosphorylated GSK3\u03b2 at serine 9 (pGSK3\u03b2-ser9) in podocytes exposed to IgG from TG patients and calculated the ratio of pGSK3\u03b2-ser9 to total GSK3\u03b2. SIGNOR-279142 0.263 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 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-144795 0.502 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5C protein P41229 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-273468 0.8 PRKCA protein P17252 UNIPROT RAB37 protein Q96AX2 UNIPROT down-regulates activity phosphorylation Thr172 YGVPFLEtSAKTGMN 9606 29312551 t miannu PKCalpha phosphorylates Rab37 on threonine 172.|These data therefore supported a mechanism by which PKCalpha blocks Rab37 mediated cargos secretion by facilitating the dissociation of phosphorylated Rab37 from its targeting vesicles. SIGNOR-278322 0.2 PP1 proteinfamily SIGNOR-PF54 SIGNOR TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t lperfetto Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-264670 0.2 PRKDC protein P78527 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-273531 0.2 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1150 LERGRKVsIVSKPVL 9606 BTO:0000887;BTO:0001260 19103606 t gcesareni Rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser(1150) and attenuated p190a rhogap activity in cos7 cells. SIGNOR-182849 0.414 CYLD protein Q9NQC7 UNIPROT CCND1 protein P24385 UNIPROT up-regulates 9606 BTO:0001286 16713561 f gcesareni Cyld was also recently shown to deubiquitylate the p50 and p52 co-activator bcl-3, leading to both cyclin d1 expression and proliferation in keratinocytes SIGNOR-146777 0.391 SPTAN1 protein Q13813 UNIPROT Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR form complex binding 9606 24302288 t lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266026 0.575 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE -1 12297295 t llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  SIGNOR-251026 0.704 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 t Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. SIGNOR-248425 0.2 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 0.8 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248500 0.318 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 0.727 IFNL3 protein Q8IZI9 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96246 0.848 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 0.2 PRKN protein O60260 UNIPROT DNM1L protein O00429 UNIPROT down-regulates quantity ubiquitination 9606 27597885 t miannu Parkin interacts with and subsequently ubiquitinates Drp1, thus promoting its proteasome dependent degradation .|We have demonstrated that parkin promotes Drp1 degradation after OGDR insult. SIGNOR-278589 0.2 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 0.936 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 0.813 MAP3K14 protein Q99558 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation 9606 20651737 t lperfetto As nik levels increase, nik presumably becomes activated by autophosphorylation (p). SIGNOR-167063 0.2 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 0.89 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 0.8 CD3G protein P09693 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates 9606 BTO:0000782 17668895 f gcesareni Tcr stimulation also activates the mitogen- and stress-activated kinases (msk) downstream of erk1/2. SIGNOR-157148 0.2 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 0.2 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Leu649 NKGAIIGlMVGGVVI -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261783 0.489 DSCAM protein O60469 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264279 0.2 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 t miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262851 0.415 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation -1 22306293 t inferred from family member PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In¬†vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor SIGNOR-270312 0.2 PPP2CB protein P62714 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 8650155 t gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity SIGNOR-252636 0.508 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 0.66 RASGEF1B protein Q0VAM2 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-161481 0.299 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu273 ANTPHLReLHLDNNK -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256352 0.61 MAPK1 protein P28482 UNIPROT AEBP1 protein Q8IUX7 UNIPROT up-regulates activity phosphorylation Thr621 GEPEFRYtAGIHGNE 10090 BTO:0000944 15654748 t miannu We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1. SIGNOR-262897 0.2 CAMK2D protein Q13557 UNIPROT ITPR2 protein Q14571 UNIPROT down-regulates activity phosphorylation Ser150 EKNAMRVsLDAAGNE 9534 BTO:0001538 23019322 t miannu Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability. SIGNOR-262692 0.308 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 0.546 prazosin chemical CHEBI:8364 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258469 0.8 PAX8 protein Q06710 UNIPROT SLC3A1 protein Q07837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000671 15673291 f miannu Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney. SIGNOR-254907 0.251 PAK4 protein O96013 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 22173096 t lperfetto Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation. SIGNOR-191557 0.286 PTPN1 protein P18031 UNIPROT PITX1 protein P78337 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr160 LDLCKGGyVPQFSGL 9606 27752061 t lperfetto PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival. SIGNOR-276974 0.354 SRC protein P12931 UNIPROT DAG1 protein Q14118 UNIPROT down-regulates phosphorylation Tyr892 PYRSPPPyVPP 9606 BTO:0000887;BTO:0001103 12795607 t lperfetto Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location SIGNOR-101655 0.55 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 0.873 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser46 SASGSAFsPYPGSAA -1 15133517 t miannu We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation. SIGNOR-263052 0.2 TERT protein O14746 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 18680434 t lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity SIGNOR-263334 0.7 CHEK1 protein O14757 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser47 EVVGGTDsSMDVFHL 9606 14585975 t llicata We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha. SIGNOR-118913 0.536 NFY complex SIGNOR-C1 SIGNOR TOP2A protein P11388 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25328138 t lperfetto The expression of human TOP2A is controlled by its promoter region that contains two GC boxes and five CCAAT boxes. NF-Y recognizes and binds to the ICBs. This binding of NF-Y to the TOP2A promoter can be promoted by HMGB1/2 and inhibited by pRb. SIGNOR-242526 0.271 PLK2 protein Q9NYY3 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation 9606 29448085 t miannu Other investigators have demonstrated that Plk2 phosphorylates mutant p53 in a positive feedback loop. SIGNOR-278980 0.592 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 t gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases SIGNOR-62582 0.765 Elongator complex complex SIGNOR-C466 SIGNOR TUBA1C protein Q9BQE3 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-269720 0.255 ANGPT1 protein Q15389 UNIPROT TIE1 protein P35590 UNIPROT up-regulates binding 9606 11172728 t gcesareni We reasoned that there may be cooperative interactions among the angiopoietins (i.e., ligands for tie2) and tie1, the orphan receptor. SIGNOR-105199 0.451 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 93934 BTO:0000475 17431006 t lperfetto One such gene was identified, encoding steroidogenic acute regulatory protein (StAR), which showed 24-h changes in expression in the F1 follicle coinciding with those of Per2. Evidence that StAR gene expression is clock driven was obtained by showing that its 5' flanking region contains E-box enhancers that bind to CLOCK/BMAL1 heterodimers to activate gene transcription SIGNOR-253700 0.285 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 0.8 PDGFRA protein P16234 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 24743741 f To further investigate the signaling pathway through which PDGFRα promotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα SIGNOR-254376 0.346 FOXO1 protein Q12778 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0000007 25510553 t miannu FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription. SIGNOR-263496 0.596 TP53 protein P04637 UNIPROT FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9841917 f Nuclear p53 amattioni Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53 SIGNOR-62379 0.404 Gbeta proteinfamily SIGNOR-PF4 SIGNOR DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation 9606 15632084 t inferred from 70% family members amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 SIGNOR-270116 0.2 AKT1 protein P31749 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 t lperfetto Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1. SIGNOR-252465 0.729 JMJD1C protein Q15652 UNIPROT H3-4 protein Q16695 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-265170 0.2 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 0.759 PINK1 protein Q9BXM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation 9606 35059394 t miannu Simultaneously overexpressing PINK1 significantly reduced the levels of exogenous total and phosphorylated tau proteins (Figures 4A,B,E).|Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment. SIGNOR-279250 0.384 PTK2 protein Q05397 UNIPROT ARHGAP42 protein A6NI28 UNIPROT up-regulates activity phosphorylation Tyr376 MDGKEPIyTLPAIIS 9606 32331391 t miannu FAK and Src Mediated Phosphorylation of GRAF3 at Y376 Promotes Allosteric Activation. SIGNOR-280097 0.309 NatB complex SIGNOR-C416 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. SIGNOR-267232 0.7 DAPK1 protein P53355 UNIPROT SNCA protein P37840 UNIPROT up-regulates quantity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 32624505 t miannu We demonstrated that DAPK1 directly phosphorylates \u03b1-synuclein at Ser129, and induces the formation of insoluble \u03b1-synuclein aggregates. SIGNOR-278440 0.27 FOXE1 protein O00358 UNIPROT MSX1 protein P28360 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21177256 f miannu The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. SIGNOR-254173 0.385 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-145292 0.2 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267296 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 t lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-249455 0.2 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 0.7 PELI1 protein Q96FA3 UNIPROT MDM4 protein O15151 UNIPROT up-regulates activity ubiquitination 9606 29523541 t miannu We found that Peli1 induces Mdmx ubiquitination without promoting its degradation, which leads to the cytoplasmic localization of Mdmx and subsequent activation of p53 function. SIGNOR-278773 0.434 FOXP1 protein Q9H334 UNIPROT HIP1R protein O75146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 23884370 f miannu Hip1r was confirmed as a direct foxp1 target / hip1r repression by foxp1 SIGNOR-202370 0.293 PHB2 protein Q99623 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation. SIGNOR-235843 0.365 TNFRSF1A protein P19438 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates 9606 10795740 t We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-256251 0.832 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 9020361 t lperfetto NIK binds to Traf2 and stimulates NF-kappaB activity. SIGNOR-46215 0.586 LETM1 protein O95202 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10090 29123128 t lperfetto LETM1 is a mitochondrial inner membrane protein and several reports suggest that it mediates mitochondrial Ca2+ uptake and extrusion in a gradient-dependent manner SIGNOR-262541 0.8 3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N,N-dimethyl-2-oxo-1H-indole-6-carboxamide chemical CHEBI:91423 ChEBI MAP2K5 protein Q13163 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190374 0.8 MMP28 protein Q9H239 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-272372 0.7 CDK1 protein P06493 UNIPROT SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr62 RRPESFTtPEGPKPR 9606 18490441 t lperfetto Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase SIGNOR-265258 0.419 GTF2IRD1 protein Q9UHL9 UNIPROT GTF2I protein P78347 UNIPROT down-regulates 9534 BTO:0004055 11438732 f lperfetto Here we describe a repressor (MusTRD1/BEN) that appears to specifically regulate the nucleocytoplasmic shuttling of TFII-I. Nuclear exclusion of TFII-I results in a repression of its target reporter gene, and such repression can be alleviated when MusTRD1/BEN is retained in the cytoplasm through targeted mutation. SIGNOR-268534 0.446 diethylstilbestrol chemical CHEBI:41922 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258597 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr171 ETSKSFVtPPQSHFV 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276907 0.429 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser134 DGATNNLsRSNSDES 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276291 0.772 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 0.755 POLR1E protein Q9GZS1 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-266153 0.797 PRL protein P01236 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 12679477 f Regulation miannu PRL inhibits lipoprotein lipase activity in human white adipose tissue SIGNOR-251851 0.328 PPP2CB protein P62714 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 17188031 t We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. SIGNOR-248597 0.2 HSPA5 protein P11021 UNIPROT ATF6 protein P18850 UNIPROT down-regulates activity binding 9606 31226023 t miannu Similar to PERK and IRE1, ATF6 is activated by ER stress-induced dissociation from GRP78 SIGNOR-260179 0.821 KRAS protein P01116 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 BTO:0003104 10082541 f lperfetto A constitutively active Ras protein [Ras(G12V)] regulates the stable expression of the NFIL3 transcription factor through both the Raf-MAPK and PI3-K pathways. SIGNOR-242757 0.2 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 0.413 MAPK1 protein P28482 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser455 SIDSEPGsPLLDDAK 9606 14988395 t lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-123045 0.358 Riluzole chemical CHEBI:8863 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258053 0.8 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 0.864 CUDC-101 chemical CID:24756910 PUBCHEM HDAC5 protein Q9UQL6 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-262261 0.8 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 0.385 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 0.446 MAPK14 protein Q16539 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Ser796 RSINKLDsPDPFKLN 9606 24269888 t lperfetto Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis SIGNOR-203315 0.345 CEBPA protein P49715 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004408 19620402 f miannu The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression. SIGNOR-253769 0.308 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 0.418 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 0.7 domperidone chemical CHEBI:31515 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258721 0.8 CDH1 protein P12830 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265863 0.96 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK -1 10202147 t done miannu  In this report, we identify Tyr319 as a functionally important phosphorylation site in the ZAP-70 interdomain B region. Phosphorylation of Tyr319 promoted the association of ZAP-70 with the SH2 domains of two key signaling molecules, Lck and PLC-gamma1. These studies suggest that Tyr319 phosphorylation is required for the assembly of a ZAP-70-containing signaling complex that leads to the activation of the PLC-gamma1- and Ras-dependent signaling cascades in antigen-stimulated T cells. SIGNOR-273948 0.619 FZD5 protein Q13467 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 t areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. SIGNOR-258969 0.67 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr27 SHHSGLEyADPEKFA 9606 15504032 t lperfetto Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1. SIGNOR-129961 0.676 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 0.528 methiothepin chemical CHEBI:64203 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258853 0.8 SMO protein Q99835 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 28709001 f We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling. SIGNOR-255907 0.2 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 0.244 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism SIGNOR-252054 0.732 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 0.317 GSK2126458 chemical CID:25167777 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252645 0.8 CCL19 protein Q99731 UNIPROT CCR7 protein P32248 UNIPROT up-regulates activity binding 9606 BTO:0000007 19497875 t CCL19 and CCL21 are endogenous agonists for the seven-trans membrane receptor CCR7. SIGNOR-278123 0.784 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 9722576 t tpavlidou 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-59750 0.2 PRKAA1 protein Q13131 UNIPROT NAMPT protein P43490 UNIPROT up-regulates quantity transcriptional regulation 10090 18477450 f gcesareni Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt SIGNOR-238598 0.298 CSNK2A1 protein P68400 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser137 LSEDEYYsEEERNAK 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276903 0.318 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264980 0.8 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity ubiquitination 9606 21799911 t By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. SIGNOR-259996 0.645 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT up-regulates activity phosphorylation Ser585 SEPVAKEsTEASKEP 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-262743 0.331 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 23151663 t gcesareni Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase SIGNOR-199641 0.456 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 0.674 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 t lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235590 0.8 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr302 DYGMMSDyGTARRTG -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246504 0.922 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells. SIGNOR-100774 0.716 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 UNIPROT up-regulates activity binding -1 14662005 t Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. SIGNOR-268421 0.8 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 0.2 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates 9606 11777913 f gcesareni Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126. SIGNOR-113566 0.433 TRAM-34 chemical CHEBI:34990 ChEBI KCNN4 protein O15554 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-207426 0.8 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser1132 RDRVRSMsGGHGLRV -1 27451907 t miannu SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.  SIGNOR-277265 0.579 FGF17 protein O60258 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-42365 0.687 AKT1 protein P31749 UNIPROT ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. SIGNOR-252512 0.367 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 18550549 t gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. SIGNOR-178880 0.272 SAR1A protein Q9NR31 UNIPROT SEC23A protein Q15436 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-265299 0.823 AKAP8L protein Q9ULX6 UNIPROT DHX9 protein Q08211 UNIPROT up-regulates activity binding 9606 11402034 t miannu We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA. SIGNOR-260950 0.544 MAPK14 protein Q16539 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation 9606 20626350 t gcesareni Jnk and p38 mapk activation have antagonistic effects in many cases. From a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab2 SIGNOR-166605 0.304 PRKACB protein P22694 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-163772 0.274 TGFB3 protein P10600 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 t miannu T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation SIGNOR-104798 0.866 PPP1CA protein P62136 UNIPROT CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 t gcesareni Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus. SIGNOR-118917 0.501 NTF3 protein P20783 UNIPROT NTRK3 protein Q16288 UNIPROT up-regulates binding 9606 1653651 t gcesareni Trkc, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. SIGNOR-20699 0.849 PI-103 chemical CHEBI:90524 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206175 0.8 PLK3 protein Q9H4B4 UNIPROT VRK1 protein Q99986 UNIPROT up-regulates phosphorylation Ser342 DDGKLDLsVVENGGL 9606 19103756 t llicata Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process. SIGNOR-182858 0.474 4'-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile chemical CID:9843116 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-257759 0.8 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 0.599 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 0.446 BAG1 protein Q99933 UNIPROT STUB1 protein Q9UNE7 UNIPROT up-regulates activity binding 9534 BTO:0001538 11676916 t miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association SIGNOR-272587 0.54 ATR protein Q13535 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 17526493 t gcesareni We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint. SIGNOR-155214 0.785 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118031 0.717 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 18303014 t lperfetto The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner SIGNOR-216627 0.263 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 0.398 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 0.415 ACP1 protein P24666 UNIPROT PKM protein P14618 UNIPROT up-regulates activity dephosphorylation 9606 30251652 t miannu Indeed, it is evident that LMW-PTP, hydrolyzing phosphotyrosine residues, contributes to maintain PKM2 in its active form.|We speculate that this effect is in large part due to LMW-PTP inhibition, which leads a fast PKM2 phosphorylation and inactivation.|we demonstrate that in melanoma cells the overexpression of LMW-PTP is functional to maintain PKM2 in its dephosphorylate status – the tetrameric, “full active” form - which is retained in the cytoplasm SIGNOR-277134 0.279 L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity precursor of 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-266955 0.8 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268278 0.8 BRK1 protein Q8WUW1 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-261875 0.847 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A6/b4 integrin complex SIGNOR-C174 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-259004 0.341 ABL1 protein P00519 UNIPROT FUS protein P35637 UNIPROT down-regulates activity phosphorylation Tyr526 QDRRERPy 9606 37071594 t miannu Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS. SIGNOR-280168 0.325 UNC13A protein Q9UPW8 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 t miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. SIGNOR-263971 0.455 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser178 EENVSDGsPNAGSVE 9606 10831586 t lperfetto Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability. SIGNOR-244517 0.2 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates gtpase-activating protein 9606 9641915 t gcesareni The guanine nucleotide exchange factor (gef) for rho, p115 rhogef, has an amino-terminal region with similarity to rgs proteins. Recombinant p115 rhogef and a fusion protein containing the amino terminus of p115 had specific activity as gtpase activating proteins toward the alpha subunits of the g proteins g12 and g13, but not toward members of the gs, gi, or gq subfamilies of galpha proteins. This gef may act as an intermediary in the regulation of rho proteins by g13 and g12. SIGNOR-58413 0.608 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 0.782 KRAS protein P01116 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT up-regulates 9606 BTO:0001271 9949177 f fstefani Bcr-abl_mediated ras activation is crucial for the ability of bcr-abl to activate gckr and is consistent with the previously known requirement for ras in bcr-abl_induced sapk activation how ras activates gckr remains enigmatic. SIGNOR-64262 0.2 PRKCA protein P17252 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity phosphorylation Ser18 KRRRTGGsLRGNPSS 9606 BTO:0000567 28850619 t miannu Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation. SIGNOR-277249 0.345 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 0.832 IFNG protein P01579 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003355 18647246 f miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. SIGNOR-252408 0.386 SNAI2 protein O43623 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 f miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. SIGNOR-255170 0.452 SLC12A2 protein P55011 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity 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-264986 0.8 CDK1 protein P06493 UNIPROT RNMT protein O43148 UNIPROT up-regulates activity phosphorylation Thr77 SSSCGKDtPSKKRKL 9606 BTO:0000007 26942677 t lperfetto We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. SIGNOR-265501 0.255 HDAC5 protein Q9UQL6 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 11062529 t gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. SIGNOR-84029 0.71 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 15221015 t gcesareni Wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. SIGNOR-126128 0.731 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain SIGNOR-137255 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 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 0.744 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 0.279 DUSP4 protein Q13115 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity dephosphorylation 10116 7535768 t inferred from 70% of family members Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK SIGNOR-269933 0.762 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 0.421 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 0.78 FADS2 protein O95864 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-267908 0.8 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr331 PYSEYFEyFAPDFTL -1 30317579 t miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  SIGNOR-277486 0.385 GSK3B protein P49841 UNIPROT GPHN protein Q9NQX3 UNIPROT down-regulates phosphorylation Ser270 LSTTPSEsPRAQATS 9606 BTO:0000142 23408424 t miannu Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain SIGNOR-200957 0.283 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 0.7 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 0.8 ACTL6B protein O94805 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270740 0.71 AKT proteinfamily SIGNOR-PF24 SIGNOR HK2 protein P52789 UNIPROT up-regulates activity phosphorylation Thr473 QHRARQKtLEHLQLS 9606 BTO:0003324 25323588 t miannu Hexokinase II is phosphorylated by Akt leading to increased mitochondrial binding and mitochondrial protection.We found that Akt, activated by receptor agonists, translocates to mitochondria and phosphorylates HK-II at Thr473, a critical step in Akt-mediated mitoHK-II increase and protection in cardiomyocytes SIGNOR-267576 0.2 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser121 PTEEEEEsESEDSED 9606 16308564 t lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. SIGNOR-142343 0.2 SLC2A2 protein P11168 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 25421524 t The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. SIGNOR-267385 0.8 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity binding 10029 12242332 t miannu Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. SIGNOR-256210 0.692 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 0.272 RDH10 protein Q8IZV5 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-265119 0.8 AKAP11 protein Q9UKA4 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 26088133 t lperfetto A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). SIGNOR-264818 0.425 CSNK2A1 protein P68400 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-250877 0.379 LIG4 protein P49917 UNIPROT Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR form complex binding -1 19837014 t miannu The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. SIGNOR-264533 0.951 EEF1A2 protein Q05639 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-269525 0.8 PAK6 protein Q9NQU5 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser187 LNSAAYSsPKLRGTL 9606 25726523 t miannu In addition, PAK5 knockdown also markedly reduced the association of GATA1 with HDAC3/4.|PAK5 phosphorylates the transcription factor GATA1 mainly at Ser161 and Ser 187, phosphorylated GATA1 recruits more HDAC3/4 to the promoter of E-cadherin and consequently suppresses the transcription of E-cadherin gene and promotes the EMT of breast cancer cells. SIGNOR-278415 0.2 PAK6 protein Q9NQU5 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 25726523 t miannu In addition, PAK5 knockdown also markedly reduced the association of GATA1 with HDAC3/4.|PAK5 phosphorylates the transcription factor GATA1 mainly at Ser161 and Ser 187, phosphorylated GATA1 recruits more HDAC3/4 to the promoter of E-cadherin and consequently suppresses the transcription of E-cadherin gene and promotes the EMT of breast cancer cells. SIGNOR-278416 0.2 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 0.2 ERN1 protein O75460 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates activity 9606 31226023 f miannu The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK) SIGNOR-260177 0.316 ICOS protein Q9Y6W8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 18641334 t ICOS ligation in concert with TCR stimulation results in strong PI3K activation in T lymphocytes. The ICOS cytoplasmic tail contains an YMFM motif that binds the p85alpha subunit of class IA PI3K, similar to the YMNM motif of CD28, suggesting a redundant function of the two receptors in PI3K signaling. SIGNOR-272539 0.497 PRKACA protein P17612 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Ser320 ASPGRPSsVDTLLSP 9606 21085490 t lperfetto Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene SIGNOR-169853 0.314 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity dephosphorylation 9606 23015147 t Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT). SIGNOR-253329 0.825 LCK protein P06239 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 17998336 t inferred from 70% of family members gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. SIGNOR-269899 0.2 POU1F1 protein P28069 UNIPROT TSHB protein P01222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 10931853 t scontino CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-β promoter. The human TSH-β promoter contains three well defined Pit-1 DNA-binding sites. SIGNOR-267205 0.438 CDK2 protein P24941 UNIPROT USP37 protein Q86T82 UNIPROT up-regulates activity phosphorylation Ser628 MVNSCITsPSTPSKK 9606 SIGNOR-C83 21596315 t lperfetto There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity SIGNOR-265045 0.447 SB-202190 chemical CHEBI:79090 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206694 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr227 PAPPEGAtPTSPVGH 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-252954 0.714 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252883 0.412 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250554 0.2 BRAF protein P15056 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates quantity phosphorylation Tyr221 HQYFMTEyVATRWYR 9606 29483645 t miannu Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD. SIGNOR-278353 0.292 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249488 0.703 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 BTO:0002572 18498745 t lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 SIGNOR-236599 0.788 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 0.473 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 0.366 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr250 NSCTPITtPELTTPC 9606 BTO:0000093 17130135 t We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation SIGNOR-253014 0.2 MAP3K11 protein Q16584 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 9733513 f gcesareni This scaffold protein selectively enhanced jnk activation by the mlk signaling pathway. SIGNOR-59884 0.324 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 0.2 ATR protein Q13535 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation 9606 29192227 t miannu Phosphorylation of UPF1 by the PIKKs SMG1, ATM and ATR is stimulated in response to DNA damage. SIGNOR-278911 0.368 PTEN protein P60484 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity binding 9606 BTO:0000007 25829446 t irozzo Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity. SIGNOR-259190 0.62 MAOB protein P27338 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264004 0.8 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser466 DEDDGEFsDDSGADQ 9606 BTO:0000007 11500362 t llicata The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo. SIGNOR-250787 0.324 CSNK2A1 protein P68400 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Ser215 IKEEDTPsDNDSGIC 9606 BTO:0000567 23123191 t miannu By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.  SIGNOR-276425 0.2 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser245 KPGALSNsESIPTID 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250598 0.29 ALDH1A1 protein P00352 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-265123 0.8 CDK1 protein P06493 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 12791267 t miannu We find that both Emi1 phosphorylation by cyclin and Cdc2 and phosphorylation on a consensus site (DSGxxS) direct recruitment of betaTrCP and subsequent Emi1 ubiquitination and destruction. SIGNOR-279143 0.753 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268383 0.7 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248409 0.788 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 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-257908 0.8 CDX2 protein Q99626 UNIPROT FUT2 protein Q10981 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000182;BTO:0000391 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-254610 0.2 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 0.428 MAP1LC3A protein Q9H492 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe. SIGNOR-191543 0.855 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t esanto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-146224 0.519 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 0.248 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively.  SIGNOR-277895 0.254 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 0.7 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559.  SIGNOR-273736 0.291 CDK5 protein Q00535 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Ser85 HQQPQSSsPVYGSSA 9606 14970194 t miannu Thus, phosphorylation of paxillin is involved in NGF-induced neurite extension of PC-12 cells, probably through regulating focal adhesion organization.|cdk5 and p38MAPK phosphorylates Ser 85 on paxillin in vitro. SIGNOR-278921 0.377 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 14766232 t lperfetto The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and _-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and _-catenin SIGNOR-247058 0.46 CBLC protein Q9ULV8 UNIPROT RET protein P07949 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24466333 t miannu Here we show that Cbl-c binds wild-type and MEN2A isoforms of the receptor tyrosine kinase, RET, and that Cbl-c enhances ubiquitination and degradation of activated RET.|We show that Cbl-c negatively regulates RET by ubiquitinating and downregulating the activated RTK while Enigma positively regulates activated RET by preventing Cbl-c binding to RET and thus preventing RET ubiquitination and degradation while promoting RET mitogenic signaling. SIGNOR-278674 0.368 MED9 protein Q9NWA0 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-266680 0.669 ILK protein Q13418 UNIPROT NACA protein Q13765 UNIPROT up-regulates phosphorylation Ser43 PELEEQDsTQATTQQ 9606 15299025 t lperfetto Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase. SIGNOR-127694 0.426 SRC protein P12931 UNIPROT PDCD6IP protein Q8WUM4 UNIPROT down-regulates activity phosphorylation Tyr319 KKDNDFIyHDRVPDL 9606 15557335 t miannu Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. SIGNOR-263201 0.393 MT-ND1 protein P03886 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262143 0.814 estramustine chemical CHEBI:4868 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation 9606 14755680 t miannu A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. SIGNOR-259296 0.8 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 0.2 GPR55 protein Q9Y2T6 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256670 0.2 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216647 0.504 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230396 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-67396 0.434 RPL22 protein P35268 UNIPROT RPL22L1 protein Q6P5R6 UNIPROT down-regulates 9606 23990801 f miannu We find that rpl22 directly represses expression of rpl22l1 mrna by binding to an internal hairpin structure. SIGNOR-202600 0.413 TNF protein P01375 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 11287630 f lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase SIGNOR-244458 0.48 SCF-SKP2 complex SIGNOR-C136 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 25733682 t miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  SIGNOR-276889 0.288 CREBBP protein Q92793 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-253813 0.2 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 0.8 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 0.8 IRX1 protein P78414 UNIPROT PTGER1 protein P34995 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261656 0.2 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 0.658 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 0.2 MRPL15 protein Q9P015 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262378 0.702 CDK5 protein Q00535 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL 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-154405 0.481 MDM2 protein Q00987 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity ubiquitination 9606 18665269 t miannu Mdm2 Induces Mono-Ubiquitination of FOXO4.|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity. SIGNOR-278656 0.63 Goserelin chemical CHEBI:5523 ChEBI LHCGR protein P22888 UNIPROT up-regulates activity chemical activation 9606 BTO:0001033 11900209 t miannu LHRH analogues, such as goserelin, reduce circulating concentrations of oestrogen in premenopausal women via an inhibitory effect on the hypothalamic–pituitary–ovarian axis. At the cellular level, LHRH analogues bind to LHRH receptors on pituitary gland cells, an action which causes an initial surge in the secretion of luteinizing hormone (LH). Once bound to ligand, these LHRH receptors form clusters, which are then sequestered within the cell, thereby reducing the number of unoccupied LHRH receptors. SIGNOR-259162 0.8 NMDA receptor_2C complex SIGNOR-C349 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264224 0.748 TADA3 protein O75528 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269584 0.758 GSK3B protein P49841 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 20466847 t miannu HG activates GSK3beta, which phosphorylates IRS1 at serine 332, leading to the ubiquitination and proteasome mediated degradation of IRS1. SIGNOR-279183 0.454 Stress_granules phenotype SIGNOR-PH124 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260866 0.7 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 0.433 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162318 0.601 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT down-regulates phosphorylation Thr33 SLVDKENtPPALSGT 9606 22632967 t gcesareni We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability. SIGNOR-197630 0.504 KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 15526160 t miannu C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit SIGNOR-254954 0.614 CHEK1 protein O14757 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation 9606 32345958 t miannu Phosphorylation of Cdh1 by Chk1 promotes recognition of Cdh1 by SCF betaTRCP1.|These data suggest that Chk1 negatively regulates APC/C Cdh1 activity by both promoting Cdh1 destruction and by destabilizing its association with the APC/C. SIGNOR-278396 0.301 WIPI1 protein Q5MNZ9 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-268477 0.606 FLT3 protein P36888 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 10080542 t gcesareni FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc SIGNOR-245060 0.604 LPAR4 protein Q99677 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256785 0.385 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 0.896 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 0.2 KLF15 protein Q9UIH9 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 15664998 f lperfetto Moreover, KLF15 and C/EBPalpha acted synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes. SIGNOR-235331 0.436 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 21945940 t lperfetto Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion. SIGNOR-216568 0.2 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251619 0.283 PPARG protein P37231 UNIPROT UCP1 protein P25874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 32991581 t brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, SIGNOR-263985 0.533 EPHA2 protein P29317 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates 9606 BTO:0000782 7982920 f gcesareni In keeping with the above observations, activation of eck by its ligand, b61, increased phosphatidylinositol 3-kinase activity SIGNOR-35418 0.363 3-(4-{[5-Fluoro-2-(4-methylphenyl)phenyl]methoxy}phenyl)propanoic acid chemical CID:57522038 PUBCHEM FFAR4 protein Q5NUL3 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-257491 0.8 EP300 protein Q09472 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-254259 0.2 MAPK8 protein P45983 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser358 GQISAGYsPVIDCHT 9606 BTO:0002181 23608534 t miannu Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.  SIGNOR-276492 0.374 FANCA protein O15360 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-263240 0.951 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser298 ACSSAPGsGPSSPNN 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-170144 0.364 PPP2R2A protein P63151 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0000018 33108758 t miannu Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. SIGNOR-266381 0.385 RAD51AP1 protein Q96B01 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 17996711 t miannu Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction. SIGNOR-261962 0.771 SKIL protein P12757 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 t gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad8. SIGNOR-95474 0.448 ZAP70 protein P43403 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity phosphorylation 9606 23620790 t miannu These results suggest that CBAP may serve as an adaptor or scaffold in the integrin \u03b21/CBAP/ZAP70-containing complex that, upon chemokine treatment, would allow Vav1 or ZAP70 (or both) to adopt an optimal conformation(s) for ZAP70 to phosphorylate Vav1.|Together, these results suggested that CBAP is an important component in ZAP70 dependent activation of the Vav1 and Rac1 signaling axis. SIGNOR-278390 0.838 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 0.8 LAMB1 protein P07942 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 t lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. SIGNOR-253230 0.722 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164617 0.557 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 BTO:0001573 17115028 t gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation SIGNOR-150847 0.578 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP -1 12468540 t gcesareni Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect SIGNOR-246236 0.414 regorafenib chemical CHEBI:68647 ChEBI NTRK1 protein P04629 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259212 0.8 ENMD-2076 chemical CID:16041424 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191469 0.8 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 0.8 PTPN1 protein P18031 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation 9606 28919207 t miannu PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a " gate-keeper " mechanism that ensures targeting of inactive receptors to axons to engage with ligand.|We identify a gate keeping mechanism in which TrkA receptors, destined for transcytosis, are dephosphorylated in neuronal soma by the ER-resident tyrosine phosphatase, PTP1B. SIGNOR-277081 0.378 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 PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192607 0.8 CDK2 protein P24941 UNIPROT ELK4 protein P28324 UNIPROT up-regulates activity phosphorylation Ser387 LSPVAPLsPARLQGA 9606 26028036 t miannu Phosphorylation of ELK4 at Thr194 and Ser387 by CDK2 is required for EGF-induced cell transformation. SIGNOR-278210 0.363 A5/b1 integrin complex SIGNOR-C163 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269012 0.7 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT up-regulates activity dephosphorylation -1 25624455 t miannu a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254722 0.26 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr218 PPRDFAAyRS 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail SIGNOR-45520 0.69 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206841 0.8 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000782 10347172 t gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. SIGNOR-67806 0.784 PPM1D protein O15297 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity dephosphorylation Ser137 LSEDEYYsEEERNAK 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276905 0.465 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 0.706 AARS1 protein P49588 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270450 0.8 AURKA protein O14965 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser539 TSLSPRSsLSSPSPP 9606 21878642 t llicata We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases. SIGNOR-176359 0.25 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 19279133 t flangone Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs. SIGNOR-242055 0.438 STIP1 protein P31948 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine. SIGNOR-261411 0.934 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 0.744 ECM stimulus SIGNOR-ST20 SIGNOR AE/b7 integrin complex SIGNOR-C186 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-259040 0.7 NOP10 protein Q9NPE3 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 t lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity SIGNOR-263331 0.62 FBXW11 protein Q9UKB1 UNIPROT CHUK protein O15111 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10321728 t miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  SIGNOR-272545 0.441 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity phosphorylation Ser139 DNETGTEsMVSHRRE 9606 16965538 t lperfetto Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development. SIGNOR-217845 0.637 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1F protein P30939 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-257520 0.8 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr142 SVGDEDIySGLSDQI -1 10669745 t Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. SIGNOR-251389 0.783 MAML1 protein Q92585 UNIPROT CDK8 protein P49336 UNIPROT up-regulates binding 9606 15546612 t gcesareni Mastermind recruits cycc:cdk8 to phosphorylate the notch icd and coordinate activation with turnover SIGNOR-130715 0.597 PRKACA protein P17612 UNIPROT ETV5 protein P41161 UNIPROT up-regulates activity phosphorylation Ser367 PPYQRRGsLQLWQFL 9606 BTO:0002909 11682477 t lperfetto We further show that the increase in erm transcriptional activity after pka phosphorylation is closely correlated with a drastic reduction in the dna binding of the transcription factor. These results indicate that the phosphorylation of erm by pka is involved in erm-mediated transcription and suggest that the activation of erm is probably related to conformational changes. SIGNOR-111239 0.2 SRC protein P12931 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 11152665 t lperfetto The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin SIGNOR-85938 0.444 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 0.429 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 0.792 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 t lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. SIGNOR-130381 0.612 MAPK1 protein P28482 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-140894 0.367 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 0.512 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Thr233 DDEDDSGtEES 9606 BTO:0000567 11546811 t llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  SIGNOR-251061 0.351 MECOM protein Q03112 UNIPROT PBX1 protein P40424 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 19767769 f miannu In this study, we identified pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of evi-1. Overexpression of evi-1 increased pbx1 expression in hematopoietic stem/progenitor cells SIGNOR-188155 0.424 PKA proteinfamily SIGNOR-PF17 SIGNOR ENAH protein Q8N8S7 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268285 0.2 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr682 SRTTDGVyEGVAIGG 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-274103 0.2 MRPS7 protein Q9Y2R9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-267730 0.765 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 0.2 Brivanib alaninate chemical CID:11154925 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190732 0.8 GDF5 protein P43026 UNIPROT Ossification phenotype SIGNOR-PH74 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-252419 0.7 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser144 DSPALEVsDSESDEA 9606 10618498 t lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability SIGNOR-73883 0.429 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Thr449 DDIRQNFtQLPLHKN 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177801 0.375 NBN protein O60934 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 t lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-251505 0.914 CSNK1A1L protein Q8N752 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates activity phosphorylation Ser158 LLDNSRMsCQDEGCG 9606 BTO:0000567 18411282 t done miannu However, the siRNA knockdown of CK1α1L significantly reduced the nuclear export of OREBP/TonEBP under hypotonic conditions (Fig. 5F). Taken together, these data suggest that CK1α1L is the kinase that phosphorylates Ser-158 in the regulation of OREBP/TonEBP export. SIGNOR-274111 0.2 CSNK1A1L protein Q8N752 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 19293931 t gcesareni Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms SIGNOR-184699 0.254 CCKAR protein P32238 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 10088 BTO:0000944 12853286 t Marta Tosoni Our studies indicate that CCK-A receptors inserted into NIH3T3 cells also activate RhoA through G12/13 SIGNOR-278062 0.25 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr413 DPEVAALyFPKNGDP 9606 BTO:0002181 33203880 t miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. SIGNOR-277293 0.2 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr386 ASNGNLLyIGFRGLD 9606 16251431 t gcesareni ?7 Neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinases SIGNOR-141307 0.2 RAB9A protein P51151 UNIPROT PLIN3 protein O60664 UNIPROT up-regulates activity 18195106 t lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector SIGNOR-253089 0.591 ARHGEF11 protein O15085 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260538 0.903 ARF5 protein P84085 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272152 0.7 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Thr818 LHRPRHAtVSRSLEG 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-184692 0.355 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 0.7 ABL1 protein P00519 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity phosphorylation 9606 19914245 t miannu A phosphotyrosine specific antibody indicated that MAVS was phosphorylated by c-Abl. SIGNOR-279673 0.453 MLL1 complex complex SIGNOR-C89 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268802 0.2 CNOT2 protein Q9NZN8 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268306 0.83 AR protein P10275 UNIPROT CLK3 protein P49761 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-253672 0.2 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248753 0.738 RPS15A protein P62244 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262436 0.856 KAT2B protein Q92831 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-269619 0.2 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 0.347 POM121 protein Q96HA1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262071 0.482 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 BTO:0000149;BTO:0001129 22730327 t gcesareni Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1) SIGNOR-197998 0.729 TWIST2 protein Q8WVJ9 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255500 0.2 NEK2 protein P51955 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 30266789 t miannu NEK2 Phosphorylates p53 at Ser315 and Reduces Its Stability.|These results are consistent with NEK2 inhibiting p53 transcriptional activation functions. SIGNOR-278488 0.318 CYP11A1 protein P05108 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268633 0.8 PAK1 protein Q13153 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Thr659 KIEINLStRMDHMVS 9606 BTO:0002181 33432150 t miannu Pak1 phosphorylates NLRP3 to promote inflammasome activation. SIGNOR-277547 0.2 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257478 0.8 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 12874243 t gcesareni Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity. SIGNOR-103983 0.729 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Thr240 QSSVAVGtPDYISPE 9534 BTO:0000298 11283256 t miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). SIGNOR-275975 0.2 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267906 0.8 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 0.811 PRKD1 protein Q15139 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 24840177 t lperfetto When PKD3 was knocked-down using isoform-specific shRNA (PKD3-shRNA), PAK4 activity (judged by its phosphorylation status at the activation loop using the pS474-PAK4 antibody) was decreased SIGNOR-275930 0.252 KCTD13 protein Q8WZ19 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-264236 0.377 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 0.855 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 0.464 9-HODE chemical CHEBI:72651 ChEBI GPR132 protein Q9UNW8 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-257501 0.8 PHACTR1 protein Q9C0D0 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates activity binding 9606 BTO:0001949 21939755 t lperfetto Phactr-1 was previously identified as protein phosphatase 1 (PP1) Œ±-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process. SIGNOR-264656 0.537 NEK2 protein P51955 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates activity phosphorylation 9606 27297360 t miannu Intriguingly, Nek2A is found to stabilize SuFu at least partly depending on its kinase activity, thereby triggering phosphorylation of the SuFu protein.|Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism. SIGNOR-279235 0.2 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 0.2 ATG16L1 protein Q676U5 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 20639872 t gcesareni Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors. SIGNOR-166702 0.46 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259024 0.435 FZD3 protein Q9NPG1 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 14977528 t gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-122892 0.244 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 0.2 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation. SIGNOR-126241 0.283 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu105 NNKDSHSlTTNIMEI -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263619 0.2 PRKAG1 protein P54619 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139170 0.765 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C85 21454478 t 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-172990 0.671 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-251599 0.704 CDK1 protein P06493 UNIPROT NUCKS1 protein Q9H1E3 UNIPROT down-regulates activity phosphorylation Ser181 LKATVTPsPVKGKGK -1 12413487 t miannu putative phosphorylation site for Cdk1 is present in the DNA-binding domain peptide. This site, corresponding to Ser 181 in the NUCKS primary structure, is phosphorylated in vitro by Cdk1 with a Km of approximately 35 μM [7]. Phosphorylation of Ser 181 in the synthetic, DNA-binding domain peptide reduces its affinity for DNA-by 100%. SIGNOR-261959 0.474 PRKCD protein Q05655 UNIPROT DBI protein P07108 UNIPROT up-regulates phosphorylation Thr42 ATVGDINtERPGMLD 9606 18194441 t gcesareni Acyl coenzyme a-binding protein (acbp) is phosphorylated following protein kinase c activation. SIGNOR-160393 0.2 DUSP19 protein Q8WTR2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 11959861 t gcesareni Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo. SIGNOR-117260 0.421 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 0.348 LCK protein P06239 UNIPROT CD3D protein P04234 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259929 0.571 ELF4 protein Q99607 UNIPROT CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000782 14625302 f miannu Myeloid elf1-like factor is a potent activator of interleukin-8 expression in hematopoietic cells SIGNOR-119204 0.241 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 0.639 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 0.706 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity phosphorylation 10090 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259930 0.692 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 0.576 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity phosphorylation 9606 23912711 t miannu Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.|BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by \u03b2TrCP1. SIGNOR-279009 0.376 AURKB protein Q96GD4 UNIPROT BUB1 protein O43683 UNIPROT up-regulates activity phosphorylation 9606 34861183 t miannu Although our analysis identified only one of the 15 sites implicated in Bub1-Mad1 interaction, it suggests that following its rapamycin-induced dimerization, Ipl1 phosphorylates Bub1, and potentially Mad1, to drive eSAC signaling. SIGNOR-279010 0.749 BTK protein Q06187 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity phosphorylation 9606 9751072 t miannu Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action. SIGNOR-279011 0.382 MAPK1 protein P28482 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 15116093 t miannu In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death. SIGNOR-279068 0.778 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 25875593 t irozzo C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site. SIGNOR-256367 0.953 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 0.717 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 0.342 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. SIGNOR-254973 0.7 Naloxone benzoylhydrazone chemical CID:9601084 PUBCHEM OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258422 0.8 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates 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-210056 0.289 NFYA protein P23511 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-254434 0.2 SMURF1 protein Q9HCE7 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 12519765 t lperfetto Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm SIGNOR-97064 0.882 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9534 16757346 t miannu We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ SIGNOR-261707 0.29 CDK5 protein Q00535 UNIPROT TPX2 protein Q9ULW0 UNIPROT up-regulates quantity by stabilization phosphorylation Ser486 LPITVPKsPAFALKN 9606 BTO:0003897 31272499 t lperfetto CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis SIGNOR-265100 0.272 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 0.681 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207860 0.8 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT down-regulates activity dephosphorylation 9606 11259588 t Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation SIGNOR-248696 0.353 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 0.8 ibrutinib chemical CHEBI:76612 ChEBI BTK protein Q06187 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189641 0.8 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270605 0.836 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 0.7 TLRs proteinfamily SIGNOR-PF20 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20404851 f lperfetto TLR signaling pathways can be largely classified as either MyD88-dependent pathways, which drive the induction of inflammatory cytokines, or TRIF-dependent pathways, which are responsible for the induction of type I interferon as well as inflammatory cytokines3. SIGNOR-216310 0.7 AVPR1B protein P47901 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256934 0.25 MFGE8 protein Q08431 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 10116 BTO:0000801 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-260652 0.2 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 0.542 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 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-256248 0.806 DVL2 protein O14641 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 17529994 t lperfetto Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex. SIGNOR-227920 0.653 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 10542228 t gcesareni Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2. SIGNOR-71764 0.296 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr284 LPQNDDHyVMQEHRK -1 16472662 t Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity SIGNOR-251184 0.2 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates activity cleavage Asp390 LPQLTLPdSLTSAAS 17761173 t lperfetto In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein SIGNOR-260613 0.396 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 0.542 STK4 protein Q13043 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181060 0.343 EEF1A2 protein Q05639 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-269528 0.8 PI3K complex SIGNOR-C156 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 18721898 f lperfetto Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3. SIGNOR-252705 0.58 CDON protein Q4KMG0 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-235551 0.2 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 0.8 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 0.603 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 0.906 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 0.524 MFF protein Q9GZY8 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc. SIGNOR-272983 0.7 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr543 CGKISKLyGDLKHLK -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-262872 0.2 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 0.858 JAK2 protein O60674 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Tyr693 TERGDKGyVPSVFIP 9606 BTO:0000782 16324152 t gcesareni Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity SIGNOR-142736 0.676 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72068 0.819 MAPK14 protein Q16539 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation 9606 17003045 t gcesareni We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3. SIGNOR-149890 0.2 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 BTO:0000007 12194824 t gcesareni The activation of eef2 kinase by ampk, resulting in the phosphorylation and inactivation of eef2, provides a novel mechanism for the inhibition of protein synthesis. SIGNOR-91751 0.788 CHIR 99021 chemical CHEBI:91091 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191000 0.8 AURKB protein Q96GD4 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT unknown phosphorylation Ser1303 ARKKARLsLVIRSPS 9606 20177074 t lperfetto We identified mybbp1a as a novel aurora b substrate and serine 1303 as the major phosphorylation site SIGNOR-163903 0.389 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT 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-252600 0.642 BAD protein Q92934 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 f miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254953 0.7 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 0.313 MRGPRX2 protein Q96LB1 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-257260 0.2 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 0.257 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent. SIGNOR-268788 0.8 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 0.648 SIAH1 protein Q8IUQ4 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates quantity ubiquitination 9606 18536714 t miannu Downregulation of Siah-1 inhibits HIPK2 degradation and recovery from damage, driving the cells into apoptosis|Siah-1 knockdown increases HIPK2 stability and steady-state levels, whereas Siah-1 expression facilitates HIPK2 polyubiquitination, degradation and thereby inactivation. SIGNOR-278715 0.514 DMTF1 protein Q9Y222 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261582 0.2 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003009; BTO:0000018 22549160 f irozzo The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. We found that silencing of Rac1 expression decreases NSCLC migration and proliferation [.] SIGNOR-259088 0.7 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Ser6 sKKRKFVA 9606 19059439 t Manara Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA SIGNOR-260894 0.2 BMP2 protein P12643 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-253547 0.929 AKT1 protein P31749 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Ser48 QLSLRTVsLGAGAKD 9606 BTO:0001345 25071014 t miannu We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. SIGNOR-276667 0.534 VAV1 protein P15498 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 9013873 f gcesareni Vav may link gp130 activation to downstream mapk activation in hematopoietic cells. SIGNOR-46064 0.508 PKN3 protein Q6P5Z2 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Ser428 PAEGKRLsASSTGST -1 30422386 t lperfetto These results verified the presence of a PKN3 phosphorylation motif in the sequence surrounding Ser432 and indicated that PKN3 phosphorylates p130Cas on Ser432 in vitro.|Human Ser428 of p130Cas corresponds to mouse p130Cas Ser432| SIGNOR-264574 0.2 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7824938 t gcesareni Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain. SIGNOR-33918 0.78 HRK protein O00198 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 9130713 t gcesareni Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1. SIGNOR-47794 0.472 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK3 protein Q00526 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189987 0.8 AKT1 protein P31749 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates activity phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 11274386 t lperfetto We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350 SIGNOR-252466 0.729 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 0.2 DDX17 protein Q92841 UNIPROT RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103 17011493 t lperfetto We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod. SIGNOR-149961 0.425 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 0.752 DIO1 protein P49895 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266954 0.8 GSK3B protein P49841 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser114 EEDHVDLsLSCTLVP 9606 BTO:0000093 17283049 t lperfetto Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation SIGNOR-152941 0.4 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Ser176 AKDVDQGsLCTSFVG 9606 SIGNOR-C14 9520446 t lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176. Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-55942 0.698 VRK1 protein Q99986 UNIPROT COIL protein P38432 UNIPROT up-regulates quantity by stabilization phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 26068304 t miannuccelli The active murine VRK1, but not its kinase-dead mutant (K179E), also phosphorylates coilin in Ser184 ( xref ). SIGNOR-279772 0.361 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser551 ELQAPVRsPITRSFA 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249461 0.633 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-216403 0.93 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Thr309 SDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma) SIGNOR-236785 0.732 ALK protein Q9UM73 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 27322022 t lperfetto Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K. SIGNOR-253217 0.379 PPP1CB protein P62140 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 t miannu 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-174862 0.265 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1015 MMVKRRDyLDLAAST 9606 14981541 t llicata Opn upregulation depended on the integrity of the ret/ptc kinase and tyrosines y1015 and y1062, two major ret/ptc autophosphorylation sites. ret signalling mainly depends on three key tyrosine residues: tyrosine 905, in the activation loop, whose phosphorylation stabilizes the active conformation of the catalytic domain , tyrosine 1015, a docking site for phospholipase citalic gamma and tyrosine 1062. SIGNOR-122915 0.2 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 0.767 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT up-regulates phosphorylation Ser474 KEVPRRKsLVGTPYW 9606 20926745 t gcesareni Intracellular localization;enzymatic activity, induced;cell growth, altered; SIGNOR-168301 0.2 ixazomib citrate chemical CHEBI:90939 ChEBI PSMB5 protein P28074 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194536 0.8 RB1 protein P06400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates 9606 14560017 f gcesareni We find that active rb mediates histone deacetylation on cyclin a, cdc2, topoisomerase iialfa, and thymidylate synthase promoters. We also demonstrate that this deacetylation is hdac dependent, since the hdac inhibitor trichostatin a (tsa) prevented histone deacetylation at each promoter. SIGNOR-118839 0.625 TOB1 protein P50616 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR down-regulates activity binding 9606 BTO:0000567 18377426 t miannu We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob.  SIGNOR-273616 0.663 PPARGC1A protein Q9UBK2 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates activity 9606 26971449 f lperfetto PGC-1 family transcriptional coactivators enhance the activities of the nuclear respiratory factors NRF1 and NRF2, which induce transactivation of many genes encoding mitochondria-specific proteins involved in respiratory chain, mitochondrial DNA transcription/replication and protein import/assembly SIGNOR-253391 0.71 chloroquine chemical CHEBI:3638 ChEBI ACE2 protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition 9534 32020029 t miannu Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells SIGNOR-260223 0.8 DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 f miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. SIGNOR-268396 0.7 RAB6B protein Q9NRW1 UNIPROT VPS13B protein Q7Z7G8 UNIPROT up-regulates activity binding 10116 BTO:0003102 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. SIGNOR-266870 0.2 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 0.463 CAMK2G protein Q13555 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 22888005 t gcesareni The kinase activity of camkii was essential for the activation of notch signaling. We also determined that camkii could enhance the association between notch1-ic and rbp-jk. Furthermore, the physical association between rbp-jk and smrt was substantially suppressed by camkii. We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. SIGNOR-191777 0.2 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207833 0.8 RANBP2 protein P49792 UNIPROT TNPO1 protein Q92973 UNIPROT up-regulates activity binding 9606 BTO:0001938 32161167 t lperfetto Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1 SIGNOR-262111 0.455 BMS-754807 chemical CHEBI:88339 ChEBI INSR protein P06213 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001802 19996272 t lperfetto BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR SIGNOR-262026 0.8 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 0.2 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 0.54 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217795 0.78 CSNK2A2 protein P19784 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 t llicata Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles. SIGNOR-251033 0.328 bexarotene chemical CHEBI:50859 ChEBI RXRA protein P19793 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259230 0.8 NOTCH proteinfamily SIGNOR-PF30 SIGNOR LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. SIGNOR-254336 0.2 SMAD3 protein P84022 UNIPROT CEBPB protein P17676 UNIPROT down-regulates activity binding 10090 12524424 t gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters SIGNOR-250567 0.597 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 0.7 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 0.7 FBXW8 protein Q8N3Y1 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 23142081 t miannu Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation.  SIGNOR-271939 0.46 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MCM10 protein Q7L590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 22570418 t miannu By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10. SIGNOR-272045 0.384 SOX9 protein P48436 UNIPROT CEBPD protein P49716 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19254573 t fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation SIGNOR-184283 0.272 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 0.8 estramustine chemical CHEBI:4868 ChEBI MAP1A protein P78559 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001332 1647395 t miannu Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. SIGNOR-259297 0.8 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 0.8 PBK protein Q96KB5 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 26745678 t miannu TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs. SIGNOR-278156 0.43 MAP3K8 protein P41279 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 BTO:0000567 12207013 t miannu Xplkk1 phosphorylates and activates mammalian plk / xplkk1 phosphorylates thr-210 SIGNOR-92274 0.2 NUP214 protein P35658 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR up-regulates activity relocalization 9606 12917407 t lperfetto We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import. SIGNOR-217719 0.555 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation Ser11 RPRHSIYsSDEDDED -1 7735324 t llicata For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants.  SIGNOR-250918 0.34 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 0.259 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 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-91045 0.729 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 7566348 t fstefani The ability of p42 map and p44 map kinases, glycogen synthase kinases 3 alpha and 3 beta (gsk-3 alpha and gsk-3 beta) to phosphorylate tau in transfected cos cells was investigated. Both gsk-3 alpha and gsk-3 beta phosphorylated tau to produce a phf-like state of phosphorylation but the map kinases failed to induce such a transformation in tau. SIGNOR-29364 0.429 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 0.615 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT unknown phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 20708153 t lperfetto Remarkably, lc-ms confirmed that the predominant serine phosphorylation site of the recombinant carboxy-terminal domain of c-nap1 is s2392 at the predicted consensus phosphorylation sequence and to a lesser extent s2394. SIGNOR-167492 0.321 sapitinib chemical CHEBI:132986 ChEBI SHC3 protein Q92529 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 20145185 t gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-163733 0.8 JQ1 chemical CHEBI:137113 ChEBI BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261987 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser525 TSMKPRSsRGSIFTF -1 12242273 t miannu These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins. SIGNOR-275991 0.2 MLNR protein O43193 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257016 0.435 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Ala92 PAFISEDaSGYLTSS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263576 0.42 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4517 LYMGGHGsRHSLAST 9606 15272003 t lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. SIGNOR-126958 0.2 GTF3C2 protein Q8WUA4 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-266187 0.873 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM 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-258026 0.8 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 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-258274 0.8 GLI2 protein P10070 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates NBK6142 f Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development.  SimoneGraziosi SIGNOR-269215 0.7 MRPL57 protein Q9BQC6 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-262341 0.636 CTTNBP2 protein Q8WZ74 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity binding 9606 BTO:0000938 35562389 t miannu Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. SIGNOR-269702 0.2 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 0.8 3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid chemical CID:446916 PUBCHEM GPR17 protein Q13304 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-257502 0.8 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249640 0.751 TNKS2 protein Q9H2K2 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0000142 32409565 t lperfetto Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. SIGNOR-262116 0.2 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-249605 0.346 PDHB protein P11177 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266547 0.937 MAPK12 protein P53778 UNIPROT CARM1 protein Q86X55 UNIPROT down-regulates activity phosphorylation Ser595 GPAISMAsPMSIPTN 10090 29681515 t apalma Here, we identify a role for the mitogen-activated protein kinase (MAPK) p38g/MAPK12 as a critical regulator of satellite stem cell fate through phosphorylation of Carm1. SIGNOR-255897 0.363 TRIM28 protein Q13263 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-255628 0.2 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 0.7 PGM1 protein P36871 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267932 0.8 CDK2 protein P24941 UNIPROT RNF4 protein P78317 UNIPROT up-regulates activity phosphorylation Thr26 RTREATStPEISLEA 9606 BTO:0002181 25948581 t miannu Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase.  SIGNOR-276900 0.2 CBLL1 protein Q75N03 UNIPROT ANXA2 protein P07355 UNIPROT down-regulates quantity by destabilization ubiquitination 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. SIGNOR-271473 0.2 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 0.873 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 0.892 NCOA1 protein Q15788 UNIPROT PGR protein P06401 UNIPROT up-regulates 9606 10449719 f miannu Progesterone receptor (pr) functions as a transcription factor that modulates the transcription of target genes in response to progesterone and other signals. The transcriptional activity of pr requires the involvement of coactivators such as steroid receptor coactivator-1 (src-1). SIGNOR-70149 0.683 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr451 TDPEALHyDYIDVEM 9534 BTO:0004055 9655255 t lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. SIGNOR-246351 0.572 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 20570526 t Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], SIGNOR-257851 0.8 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251595 0.704 DRAP1 protein Q14919 UNIPROT BTAF1 protein O14981 UNIPROT up-regulates activity binding 9986 15509807 t miannu We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP. SIGNOR-263918 0.504 RNMT protein O43148 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity chemical modification 9606 27422871 t lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. SIGNOR-268316 0.8 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 0.2 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257961 0.8 ETS2 protein P15036 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 11175361 f miannu Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis SIGNOR-259870 0.7 BDKRB2 protein P30411 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257090 0.458 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 0.2 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 t miannu Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro. SIGNOR-98271 0.346 ADAM17 protein P78536 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259844 0.591 SLC34A2 protein O95436 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 11009570 t lperfetto Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 SIGNOR-270578 0.8 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259019 0.399 GATA2 protein P23769 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27545880 f irozzo GATA-2 phosphorylation facilitates GATA-2 chromatin occupancy at GATA-2 target genes. GATA-2 stimulates GATA2 transcription through positive autoregulation SIGNOR-256090 0.2 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 0.534 SNRPA protein P09012 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270627 0.68 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 0.295 DDC protein P20711 UNIPROT tyramine smallmolecule CHEBI:15760 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-263994 0.8 eplerenone chemical CHEBI:31547 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18038968 t Luana Indeed, eplerenone, 1, also acts as a mineralocorticoid receptor antagonist and is used to treat numerous patients for hypertension and congestive heart failure. SIGNOR-257763 0.8 DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 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-185271 0.735 MAP1LC3A protein Q9H492 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation SIGNOR-219406 0.7 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser23 NDMKVRKsSTPEEVK 9606 BTO:0001271 22855535 t lperfetto Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization SIGNOR-198478 0.2 TBL1XR1 protein Q9BZK7 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 24243687 t miannu We showed that tblr1 physically interacts with ar and directly occupies the androgen-response elements of the affected ar target genes in an androgen-dependent manner. / we characterized tblr1 as a coactivator of ar SIGNOR-203235 0.393 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-175805 0.85 MYH9 protein P35579 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 BTO:0004953 32685004 t miannu Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. SIGNOR-269285 0.254 CDK2 protein P24941 UNIPROT FOXO1 protein Q12778 UNIPROT 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-150028 0.652 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 0.795 RPS6KA1 protein Q15418 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates activity phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 10398585 t miannu Mitogen activated ribosomal S6 kinase (p90 rsk1) phosphorylates IkappaBalpha at S32, binds IkappaBalpha in vivo, and overexpression of dominant negative p90 rsk1 inhibits degradation of IkappaBalpha in response to TPA. SIGNOR-279311 0.386 CPSF1 protein Q10570 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 14749727 t miannu 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-121646 0.941 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257986 0.8 NFATC3 protein Q12968 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 t lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. SIGNOR-251732 0.283 FBXW11 protein Q9UKB1 UNIPROT EEF2K protein O00418 UNIPROT down-regulates ubiquitination 9606 phosphorylation:Ser441;Ser445 ESENSGDsGYPSEKR;SGDSGYPsEKRGELD 22669845 t gcesareni Eef2k was degraded by the ubiquitin-proteasome system through the ubiquitin ligase scf(__trcp) (skp1-cul1-f-box protein, __-transducin repeat-containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eef2k on a canonical __trcp-binding domain SIGNOR-197730 0.436 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 0.8 GRB2 protein P62993 UNIPROT SOS2 protein Q07890 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175180 0.88 MEN1 protein O00255 UNIPROT MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255867 0.2 DIO proteinfamily SIGNOR-PF83 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20978344 f inferred from family member miannu The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. SIGNOR-270306 0.2 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 t gcesareni Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity. SIGNOR-102717 0.497 IRX1 protein P78414 UNIPROT PTGS2 protein P35354 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-261662 0.2 AKT1 protein P31749 UNIPROT 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-108508 0.586 F2RL1 protein P55085 UNIPROT SERPINB2 protein P05120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254856 0.2 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2049 DAAVVLLkNGANKDM 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-156915 0.414 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser214 ARRSRAAsSQRAEEE 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-197971 0.469 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 0.774 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-256459 0.742 HTR4 protein Q13639 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256769 0.497 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 16331690 t gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. SIGNOR-142953 0.408 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser469 IRRSGSTsPLGFARA 9606 BTO:0002181 31378785 t miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  SIGNOR-277474 0.2 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 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-259708 0.8 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 0.43 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 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-157746 0.868 estriol smallmolecule CHEBI:27974 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258585 0.8 BRD8 protein Q9H0E9 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269304 0.657 CIB2 protein O75838 UNIPROT TMC2 protein Q8TDI7 UNIPROT up-regulates activity binding 10090 BTO:0004744 28663585 t miannu  Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia. SIGNOR-269665 0.352 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 0.733 DLL4 protein Q9NR61 UNIPROT KDR protein P35968 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18339870 f gcesareni Dll4 down-regulates vascular endothelial growth factor (vegf) receptor 2 and nrp1 expression and inhibits vegf function SIGNOR-178026 0.474 PDK1 protein Q15118 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t gcesareni Human pdh1 and rat pdh2 were expressed previously and were shown to have different specific activities and the ability to be phosphorylated by pdk1 and pdk2 SIGNOR-143966 0.505 C3 protein P01024 UNIPROT C3AR1 protein Q16581 UNIPROT up-regulates activity binding 9606 cleavage:Arg671;Arg748 QPAARRRrSVQLTEK;ASHLGLArSNLDEDI 8765043 t complement C3a fragment: PRO_0000005910 lperfetto A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a. SIGNOR-263451 0.734 L-glutamate(1-) smallmolecule CHEBI:29985 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-267822 0.8 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 0.25 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 0.974 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 0.817 BRCA1-A complex complex SIGNOR-C296 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR down-regulates 25400280 f lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. SIGNOR-263226 0.7 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone chemical CHEBI:91372 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 15604286 t gcesareni Through screening a small molecule compound library developed for the phosphatidylinositol 3'-kinase-like kinase family, we identified an atp-competitive inhibitor, 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (ku-55933), that inhibits atm with an ic(50) of 13 nmol/l and a ki of 2.2 nmol/l SIGNOR-132441 0.8 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr227 KVDATADyICKVKWG 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274104 0.2 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268998 0.25 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 0.658 HNF1A protein P20823 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 f inferred from family member miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators SIGNOR-270224 0.311 PRKACA protein P17612 UNIPROT GLI1 protein P08151 UNIPROT down-regulates phosphorylation 16293631 t We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1. SIGNOR-253539 0.551 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates chemical activation 9606 8276865 t gcesareni Lpa activates its own g protein-coupled receptor(s) leading to stimulation of phospholipase c and inhibition of adenylate cyclase. SIGNOR-37368 0.8 CDK5RAP2 protein Q96SN8 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271723 0.545 HSF4 protein Q9ULV5 UNIPROT DNASE2B protein Q8WZ79 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23507146 f miannu We found that HSF4 promoted the expression and DNase activity of DLAD by directly binding to the DLAD promoter. SIGNOR-254479 0.368 H2AZ2 protein Q71UI9 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263709 0.2 NDEL1 protein Q9GZM8 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 t miannu LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex SIGNOR-252159 0.72 RAB7A protein P51149 UNIPROT PSMA7 protein O14818 UNIPROT up-regulates activity binding 10036 14998988 t Sara Rab7 Forms a Complex with the Proteasome -Subunit XAPC. In this study the proteasome alpha-subunit XAPC7 (also known as PSMA7, RC6-1, and HSPC in mammals) was identified to interact specifically with Rab7 and was recruited to multivesicular late endosomes through this interaction. SIGNOR-261303 0.343 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 0.835 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81403 0.835 F11 protein P03951 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261857 0.493 CDK5 protein Q00535 UNIPROT VRK3 protein Q8IV63 UNIPROT up-regulates activity phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 t lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation| SIGNOR-275544 0.356 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 0.59 NTN1 protein O95631 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268183 0.853 GADD45A protein P24522 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 20626350 t gcesareni Gadd45alfa appears to act as an endogenous inhibitor of the alternative p38alfa-activation pathway in t-cell, by binding to p38alfa and preventing tyr323 phosphorilation SIGNOR-166584 0.461 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Ser213 TRKLMEFsEHCAIIL 9606 BTO:0002181 9155023 t lperfetto Here we show that TbetaRII kinase is regulated intricately by autophosphorylation on at least three serine residues. Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. SIGNOR-236087 0.2 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. SIGNOR-249044 0.373 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. SIGNOR-89423 0.2 PLEKHG5 protein O94827 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260566 0.771 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 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-248513 0.408 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235975 0.914 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 0.2 MAPK8 protein P45983 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax. gcesareni We demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria 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. SIGNOR-124012 0.559 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT down-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 14517306 t Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 SIGNOR-251177 0.561 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001030 10909770 f Regulation of expression miannu The suppression of lipoprotein lipase expression in J774.2 macrophages by IFN-gamma and TNF-alpha is mediated at the transcriptional level. SIGNOR-251854 0.355 CIITA protein P33076 UNIPROT HLA-E protein P13747 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11137213 f HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA SIGNOR-254019 0.496 TEK protein Q02763 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242634 0.538 arecoline chemical CHEBI:2814 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258639 0.8 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser59 FPPSPTGsLTQDPAR 9606 16484495 t llicata We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock. SIGNOR-144570 0.282 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 8381049 t inferred from 70% family members gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. SIGNOR-270192 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274082 0.544 EGR1 protein P18146 UNIPROT PDGFC protein Q9NRA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001685 15247255 f The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter SIGNOR-254268 0.251 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr45 PGGTLFStTPGGTRI 9606 11777913 t gcesareni Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126. SIGNOR-113563 0.659 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-259462 0.8 SRC protein P12931 UNIPROT PTP4A3 protein O75365 UNIPROT down-regulates activity phosphorylation Tyr53 VRVCEVTyDKTPLEK 9606 23691193 t miannu Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification. SIGNOR-278262 0.358 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 0.826 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-252812 0.2 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr280 PKPSNPIyNEPDEPI 9606 BTO:0000782 18541536 t miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. SIGNOR-262888 0.578 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI TP53 protein P04637 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189999 0.8 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000007 10068673 t done miannu These results demonstrate that WASP, under this experimental condition, can be tyrosine-phosphorylated by the kinase activity of Btk and that the direct interaction between WASP and the SH3 domain of Btk is required for this phosphorylation to occur. SIGNOR-273958 0.743 SLK protein Q9H2G2 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates phosphorylation 9606 BTO:0000671 16316999 t gcesareni Induction of apoptosis by the ste20-like kinase slk, a germinal center kinase that activates apoptosis signal-regulating kinase and p38 SIGNOR-142665 0.253 P2RY13 protein Q9BPV8 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-256892 0.2 MAP2K4 protein P45985 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Tyr249 VEPKTETyVEANMGL 9606 10938283 t miannu Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1. SIGNOR-80619 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2A protein Q02078 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216960 0.268 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 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-263779 0.7 CREB5 protein Q02930 UNIPROT LGALS3BP protein Q08380 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002812 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253805 0.2 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 0.898 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr452 GLEKTQTtPNGSLQA 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-249310 0.433 phentolamine chemical CHEBI:8081 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258444 0.8 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr256 LKAALKLyHVSDSEG 9606 15342783 t lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton SIGNOR-247433 0.363 ELAVL4 protein P26378 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266865 0.2 SRC protein P12931 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates activity phosphorylation Tyr625 RSGTMNSyEMRKALE -1 35697802 t miannu CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation. SIGNOR-277598 0.525 BRCA1 protein P38398 UNIPROT MACROH2A1 protein O75367 UNIPROT up-regulates activity ubiquitination Lys123 KKRGSKGkLEAIITP 9606 28564596 t miannu BRCA1 Ubiquitinates K123 of mH2A1 in a Ligase-Activity-Dependent Manner. SIGNOR-278752 0.2 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT up-regulates activity phosphorylation Ser99 KLAVRLEsAWADRVR 23841590 t lperfetto Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase n the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1). Phosphorylation of PAK4 at Ser99 also mediates binding to 14-3-3 protein, and is required for the formation of a PAK4-LIMK-PKD1 complex that regulates cofilin activity and directed cell migration| SIGNOR-275939 0.479 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT unknown phosphorylation Ser440 SPLLMILsQLLPQQR -1 10608806 t llicata Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. SIGNOR-250576 0.2 NR5A1 protein Q13285 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19237537 t miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. SIGNOR-271787 0.479 pipamperone chemical CHEBI:78549 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258575 0.8 EFNB1 protein P98172 UNIPROT EPHB4 protein P54760 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52580 0.754 AURKB protein Q96GD4 UNIPROT KNL1 protein Q8NG31 UNIPROT down-regulates phosphorylation Ser24 RPVRRRHsSILKPPR 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-165502 0.2 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser448 QGYRERLsLLRSEVE 9606 20864540 t lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. SIGNOR-168049 0.252 LTC4S protein Q16873 UNIPROT glutathionate(1-) smallmolecule CHEBI:57925 ChEBI down-regulates quantity chemical modification 9606 27365393 t miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). SIGNOR-277259 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 20457810 f lperfetto Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. SIGNOR-244750 0.2 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 0.774 GSK3B protein P49841 UNIPROT BAX protein Q07812 UNIPROT up-regulates phosphorylation Ser163 GGWDGLLsYFGTPTW 9606 BTO:0000938 15525785 t lperfetto Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163 SIGNOR-130141 0.376 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 0.862 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys121 GESVYGEkRVSISEG 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275899 0.27 PRKDC protein P78527 UNIPROT AKT1 protein P31749 UNIPROT 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-252431 0.754 SKP1 protein P63208 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 t miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-255278 0.442 ATF1 protein P18846 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8999965 f miannu it was shown that both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments. SIGNOR-253742 0.2 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 0.34 JUN protein P05412 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004603 13679379 t Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  SIGNOR-261604 0.826 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser246 RGGPEPLsPFPVSPL 9606 10330152 t lperfetto The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a). SIGNOR-67524 0.596 MAPK1 protein P28482 UNIPROT PDXDC1 protein Q6P996 UNIPROT unknown phosphorylation Thr691 AGVTLPPtPSGSRTK 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-262759 0.2 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 0.2 TET3 protein O43151 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 t miannu Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation SIGNOR-200729 0.443 MRPL2 protein Q5T653 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262374 0.721 acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267108 0.8 MAPK9 protein P45984 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188 SIGNOR-124031 0.2 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 0.732 FBLIM1 protein Q8WUP2 UNIPROT FLNC protein Q14315 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-266107 0.789 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 0.2 Gbeta proteinfamily SIGNOR-PF4 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-270027 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254355 0.7 ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259064 0.7 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 0.654 ARHGEF25 protein Q86VW2 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-260544 0.835 CSNK2A1 protein P68400 UNIPROT EIF3J protein O75822 UNIPROT up-regulates activity phosphorylation Ser127 LKKLQEEsDLELAKE 9606 BTO:0000007 25887626 t miannu CK2 phosphorylates the eIF3j subunit at Ser127. CK2-phosphorylation of eIF3j triggers its association with the eIF3 complex. SIGNOR-266402 0.326 EID1 protein Q9Y6B2 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 11073990 f lperfetto Thus, EID-1 binds both Rb and p300 and is a novel repressor of MyoD function. SIGNOR-253378 0.343 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 15356634 t gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128735 0.549 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 f fspada Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-178281 0.7 CTNND1 protein O60716 UNIPROT ZBTB33 protein Q86T24 UNIPROT down-regulates 9606 23481205 f gcesareni Nuclear signaling is affected by the interaction ofp120with kaiso, a transcription factor regulatingwnt-responsive genes. in addition, p120 cytoplasmic localization results in sequestration of kaiso in the cytoplasm and its inactivation SIGNOR-192369 0.824 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. SIGNOR-248619 0.59 RPS6 protein P62753 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 10090 23318442 f Luana Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program SIGNOR-264619 0.7 NLGN3 protein Q9NZ94 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-264147 0.84 MAPK3 protein P27361 UNIPROT PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 t lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. SIGNOR-249477 0.67 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp372 EFEVSFLdSPGAQAQ 9606 BTO:0000567 11815631 t Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage SIGNOR-260603 0.396 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 0.7 PRKCD protein Q05655 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates activity phosphorylation Ser78 PAYSRALsRQLSSGV 9606 22974980 t miannu Radioactive kinase assays confirmed that PKC\u03b4 phosphorylated Hsp27 at Ser78 and Ser82 ( Fig. 3 B). SIGNOR-278424 0.515 SPOP protein O43791 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0002181 16524876 t Gianni These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis. SIGNOR-268858 0.483 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR1 protein Q92633 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193558 0.8 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 0.485 ITGB2 protein P05107 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253194 0.831 ARHGAP11B protein Q3KRB8 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260468 0.49 NPPA protein P01160 UNIPROT NPR1 protein P16066 UNIPROT up-regulates binding 9606 15911069 t gcesareni Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp) SIGNOR-137600 0.887 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 9606 16733250 t lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. SIGNOR-146902 0.396 POU4F2 protein Q12837 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity binding 9606 BTO:0000093 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-241208 0.571 Mubritinib chemical CID:6444692 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194581 0.8 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 0.2 NXF1 protein Q9UBU9 UNIPROT mRNA_nuclear_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 0.7 WEE1 protein P30291 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr183 FQRLTPSyNADILLS 9606 BTO:0001033 32871104 t miannu Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. SIGNOR-277529 0.2 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 0.307 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270734 0.796 Av/b1 integrin complex SIGNOR-C175 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-277737 0.705 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 8355 BTO:0000964 8700149 t inferred from family member miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. SIGNOR-270260 0.8 TSC2 protein P49815 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor SIGNOR-93133 0.848 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250553 0.2 USP14 protein P54578 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 26523394 t lperfetto The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation SIGNOR-265057 0.448 ATF6 protein P18850 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001088 20861013 f miannu We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes. SIGNOR-253752 0.404 FURIN protein P09958 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 t Cleavage in Golgi gcesareni The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling. SIGNOR-196914 0.667 NUMA1 protein Q14980 UNIPROT TUBA8 protein Q9NY65 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-116826 0.2 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT down-regulates activity phosphorylation Tyr770 LSAPFEQySPGGQDT 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3these results suggest that y770 may negatively regulate the activation of pi 3-kinase by constitutively activated fgfr3 SIGNOR-106746 0.2 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 0.8 DLGAP4 protein Q9Y2H0 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264597 0.2 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 t lperfetto Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells. SIGNOR-134329 0.476 progesterone smallmolecule CHEBI:17026 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258705 0.8 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr349 EEPPDHQyYNDFPGK 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-64186 0.592 PGD protein P52209 UNIPROT NADP(3-) smallmolecule CHEBI:58349 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-268112 0.8 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 9335504 t llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 SIGNOR-52687 0.608 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 0.862 DISC1 protein Q9NRI5 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 t miannu Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology  SIGNOR-252162 0.58 P2RY6 protein Q15077 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-256947 0.2 ELK4 protein P28324 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20145255 t Luana Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter. SIGNOR-261592 0.2 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 0.8 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA-PK complex SIGNOR-C107 SIGNOR up-regulates activity binding -1 9442054 t miannu These proteins are NF90 and NF45, which are the 90- and 45-kDa subunits of a protein known to bind specifically to the antigen receptor response element of the interleukin 2 promoter, and the alpha, beta, and gamma subunits of eukaryotic translation initiation factor eIF-2. We also show that NF90, NF45, and eIF-2 beta are substrates for DNA-PK in vitro. In addition, recombinant NF90 promotes formation of a complex between DNA-PKcs, Ku, and DNA, and antibodies to recombinant NF90 or recombinant NF45 immunoprecipitate DNA-PKcs in vitro. Together, our data suggest that NF90, in complex with NF45, interacts with DNA-PKcs and Ku on DNA and that NF90 and NF45 may be important for the function of DNA-PK. SIGNOR-268489 0.405 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 0.2 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser362 TLKNKTEsSLLAKLE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276200 0.381 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 0.315 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity 10116 BTO:0000452;BTO:0000099 BTO:0001279 31623154 f P00441:p.Gly94Ala (mutation increasing interaction) We found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis SIGNOR-262783 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 t miannu Collectively, these data suggest that PKA destabilizes PP2Cβ upon inflammatory stimuli via phosphorylation of Ser-195 in PP2Cβ. SIGNOR-277825 0.2 U2AF1 protein Q01081 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR form complex binding 9606 8647433 t miannu The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35). SIGNOR-41945 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 f The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines SIGNOR-253587 0.7 TFPT protein P0C1Z6 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270857 0.462 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPD protein P49716 UNIPROT down-regulates binding 9606 12524424 t fspada C/ebpbeta and c/ebpdelta were found to physically interact with smad3 and smad4, and smad3 cooperated with smad4 and tgf-beta signaling to repress the transcriptional activity of c/ebps. SIGNOR-97120 0.323 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Thr62 VVGIDLGtTNSCVAV 9606 17573779 t lperfetto Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin SIGNOR-156185 0.2 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT up-regulates activity phosphorylation Thr69 VTRGDVFtMPEDEYT 10090 BTO:0000944 9733784 t llicata  Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant SIGNOR-250970 0.328 PRKCA protein P17252 UNIPROT NCF4 protein Q15080 UNIPROT up-regulates activity phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000776 34264265 t miannu In murine and guinea pig neutrophils, PKCδ is required for the phosphorylation of p40phox, a subunit of the NADPH oxidase complex (Li et al., 2016; Someya et al., 1999). In particular, it mediates phosphorylation of the threonine 154 (T154) residue of p40phox, a key regulatory step in the activation of the NADPH oxidase complex in peripheral neutrophils and B cells, in both mice and humans. In conclusion, the EBV-B cells of patients with PKCδ deficiency have impaired ROS production, associated with lower levels of phosphorylation of the cytosolic NADPH oxidase subunit p40phox by PKCδ. SIGNOR-277628 0.2 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 0.751 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 0.8 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 16420481 t The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. SIGNOR-143837 0.406 UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267483 0.2 TFIIH complex SIGNOR-C457 SIGNOR NR5A1 protein Q13285 UNIPROT up-regulates phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 17901130 t llicata In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1 SIGNOR-269355 0.2 XAV939 chemical CHEBI:62878 ChEBI CTNNB1 protein P35222 UNIPROT down-regulates 9606 19759537 f amattioni Xav939 selectively inhibits beta-catenin-mediated transcription. Xav939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. SIGNOR-188051 0.8 MRPL43 protein Q8N983 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262353 0.699 DAPK3 protein O43293 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH -1 15001356 t llicata ZIP kinase phosphorylates p21(WAF1) at Thr145 and alanine-substituted mutations in the p21(WAF1) phosphorylation site alter its ability to be phosphorylated by ZIP kinase. | Transfected ZIPK can promote the phosphorylation of p21(WAF1) at Thr145 in vivo and can increase the half-life of p21(WAF1) SIGNOR-251085 0.316 H2BC11 protein P06899 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-263699 0.2 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 0.262 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser937 ETSFRKLsFTESLTS 19531803 t lperfetto Ser940 of p105 was phosphorylated by PKA to a similar extent, whereas no phosphorylation of the same sequence occurred when Ser940 was substituted by Ala|Mechanistically, phosphorylation of p105 at Ser940 by PKA appeared to attenuate the extent of IKK-dependent phosphorylation of p105 at Ser935, which could in turn influence the rate of activation of NF-kappaB SIGNOR-260327 0.509 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 0.684 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 0.846 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 0.579 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9606 BTO:0000567 10669763 t lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. SIGNOR-74919 0.552 TSC2 protein P49815 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 9606 12172553 f gcesareni Here, we show that tsc1-tsc2 inhibits the p70 ribosomal protein s6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4e binding protein 1 (4e-bp1, an inhibitor of translational initiation). SIGNOR-91395 0.526 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265818 0.2 GSK3A protein P49840 UNIPROT FCAR protein P24071 UNIPROT down-regulates activity phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 t lperfetto GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. SIGNOR-264856 0.2 IDH complex SIGNOR-C396 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI down-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-268114 0.8 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 0.8 ETS2 protein P15036 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 11175361 f miannu the constitutive expression of ets2 in myeloblast leukemic cells induces their differentiation to macrophages SIGNOR-259871 0.7 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin SIGNOR-182840 0.595 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 0.842 MAX protein P61244 UNIPROT MXI1 protein P50539 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu The role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240314 0.558 NRG2 protein O14511 UNIPROT ERBB3 protein P21860 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.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-26881 0.82 PRKCD protein Q05655 UNIPROT CARD9 protein Q9H257 UNIPROT up-regulates activity phosphorylation Thr231 CKVERKHtLKLRHAM 9606 22265677 t miannu Here we demonstrated that protein kinase C-delta (PKCdelta) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9 and Bcl10 complex assembly and canonical NF-kappaB control. SIGNOR-278383 0.432 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates transcriptional regulation 10090 26315890 f svumbaca IL-1b was present in the sera of wild-type mice but was not detected in the sera of IRF5-/- mice SIGNOR-255340 0.292 Membrane attack complex complex SIGNOR-C313 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR up-regulates -1 30552328 f lperfetto CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers SIGNOR-263456 0.7 CCT4 protein P50991 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-272866 0.751 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000938 16923168 t The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. SIGNOR-148970 0.451 ESR1 protein P03372 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-268546 0.426 NDUFA3 protein O95167 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added SIGNOR-262155 0.795 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Ser1224 PASIMDEsVLGVSMF 9606 BTO:0000567 15737063 t lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase SIGNOR-275532 0.737 PRKAA2 protein P54646 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276838 0.2 GTF2H3 protein Q13889 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-269314 0.904 PTPRR protein Q15256 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001616 17360477 t Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. SIGNOR-248719 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252829 0.911 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY11 protein Q96G91 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-257559 0.8 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120248 0.316 PRKCD protein Q05655 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t lperfetto In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-249108 0.301 Av/b2 integrin complex SIGNOR-C176 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-257715 0.63 TRIB3 protein Q96RU7 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates activity binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271602 0.2 CDK1 protein P06493 UNIPROT CCNY protein Q8ND76 UNIPROT down-regulates activity phosphorylation 9606 30154440 t miannu Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division. SIGNOR-279012 0.595 CDH4 protein P55283 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 10090 18701479 t lperfetto Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS. SIGNOR-253103 0.273 CSNK1D protein P48730 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267998 0.719 GGCX protein P38435 UNIPROT PROZ protein P22891 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265926 0.507 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9484836 t gcesareni Ephrin-b3, a ligand for the receptor ephb3, expressed at the midline of the developing neural tube. SIGNOR-54711 0.821 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr180 EFKNIFGtPEFVAPE 9606 15611134 t gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. SIGNOR-132459 0.2 CTNNB1 protein P35222 UNIPROT FOXA2 protein Q9Y261 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22945641 f gcesareni Our study indicates that beta-catenin regulates foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation SIGNOR-198929 0.443 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser526 MSGTGMRsVTGTPYW 9606 20448038 t lperfetto Pp2ac binds to the phosphorylated mekk3 and subsequently dephosphorylate mekk3 at thr-516, ser-520, and ser-526 residues to terminate mekk3-mediated ikkbeta/Nf-kappaB Activation SIGNOR-165233 0.372 SREBF1 protein P36956 UNIPROT LRP1 protein Q07954 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980003 f miannu In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression. SIGNOR-254462 0.277 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 0.249 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates activity phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 11689711 t gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. SIGNOR-249665 0.2 RMDN3 protein Q96TC7 UNIPROT VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR form complex binding 10116 BTO:0000142 30841933 t lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. SIGNOR-262119 0.606 KAT2B protein Q92831 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates acetylation 9606 BTO:0000782;BTO:0001271 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-177749 0.602 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 0.8 SPTAN1 protein Q13813 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates activity 19102630 f lperfetto We have shown that in the nucleus alphaRIISp is involved in repair of DNA interstrand cross-links (13,14). It binds to purified DNA containing an interstrand crosslink; it colocalizes with the cross-link repair protein, XPF, in damage-induced nuclear foci after treatment of cells with a DNA interstrand cross-linking agent, and it is needed for the production of incisions by XPF at the site of an interstrand cross-link SIGNOR-263276 0.286 MRPS16 protein Q9Y3D3 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 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-261454 0.777 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT up-regulates activity phosphorylation Thr173 QPGKKLTtSCGSLAY 9606 15733851 t Manara We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173) SIGNOR-260824 0.367 IC-87114 chemical CHEBI:90686 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206193 0.8 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 0.2 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 9606 BTO:0002181 34010649 t miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-277557 0.2 GPR84 protein Q9NQS5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256847 0.277 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 0.2 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 0.848 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189996 0.8 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 0.481 KDM5D protein Q9BY66 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265336 0.2 ABL1 protein P00519 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Tyr367 TYLQSRYyRAPEIIL 9606 25944899 t Manara The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage SIGNOR-260936 0.403 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K SIGNOR-255844 0.73 PIK3CG protein P48736 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 21779497 t gcesareni The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) SIGNOR-175244 0.8 AZ 960 chemical CID:25099184 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190128 0.8 TCF12 protein Q99081 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241119 0.673 WNT1 protein P04628 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t lperfetto Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth SIGNOR-129577 0.709 HAP1 protein P54257 UNIPROT AHI1 protein Q8N157 UNIPROT up-regulates activity binding 9606 BTO:0000452 23532844 t miannu Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis. SIGNOR-269081 0.549 SMAD2 protein Q15796 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-78988 0.451 RPS4Y2 protein Q8TD47 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262448 0.2 CUDC-907 chemical CID:54575456 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191209 0.8 CREB1 protein P16220 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8999965 f miannu both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments. SIGNOR-253789 0.2 SIRT1 protein Q96EB6 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI up-regulates quantity chemical modification 9606 18662546 t miannu The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. SIGNOR-267964 0.8 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 15767678 t gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. SIGNOR-134558 0.722 CHFR protein Q96EP1 UNIPROT SMARCD1 protein Q96GM5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 t miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. SIGNOR-271459 0.307 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244357 0.2 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206905 0.8 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 0.576 APC-c complex SIGNOR-C150 SIGNOR IRS2 protein Q9Y4H2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 32554797 t miannu We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1 Consistent with the APC/C's role in degrading cell cycle regulators. Consistent with this observation, we found that APC/C inhibition decreased the polyubiquitylation of HA-tagged IRS2 in HeLa cells treated with MG132 (Fig. 2G). SIGNOR-272196 0.2 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 29958106 f miannu In adult hematopoiesis, allelic CBFβ-SMMHC expression alters hematopoietic stem cell (HSC) differentiation, with clonal expansion of the short-term HSCs and pre-leukemic myeloid progenitor cells SIGNOR-255736 0.7 CDK5 protein Q00535 UNIPROT APEX1 protein P27695 UNIPROT up-regulates activity phosphorylation Thr233 NKKNAGFtPQERQGF 9606 21727086 t miannu Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5. SIGNOR-276337 0.377 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t llicata Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation. SIGNOR-113964 0.402 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 0.2 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 0.707 RET protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 12738763 t lperfetto Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1. SIGNOR-235863 0.2 EGLN3 protein Q9H6Z9 UNIPROT BCL2L11 protein O43521-1 UNIPROT up-regulates quantity by stabilization hydroxylation Pro70 PLAPPASpGPFATRS 9606 31375625 t lperfetto EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues SIGNOR-262004 0.254 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates activity phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 32238881 t miannu Src enhances the stability of BCKDK.|We observed that, active Src distinctly phosphorylated the Y246 site of BCKDK. SIGNOR-278347 0.2 NAE complex SIGNOR-C131 SIGNOR CUL4B protein Q13620 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-243163 0.614 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser392 FKTEGPDsD -1 10884347 t llicata Our previous data has shown that cyclin A-cdk2 is the major enzyme responsible for modifying p53 at Ser315 in vivo after irradiation damage and in this report we dissect the mechanism of cyclinA-cdk2 binding to and phosphorylation of p53. SIGNOR-250751 0.81 seliciclib chemical CHEBI:45307 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206559 0.8 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity relocalization 9606 18596912 t lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-179407 0.398 AP3S2 protein P59780 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 t miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) SIGNOR-268518 0.709 JAK2 protein O60674 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation Tyr1939 CEKYGPDyVPQKSHG -1 30944118 t miannu Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.  SIGNOR-277290 0.418 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 0.338 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser533 AEMRGGRsPRPGSSA 9606 BTO:0002181 31378785 t miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  SIGNOR-277472 0.2 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159432 0.2 NODAL protein Q96S42 UNIPROT LIF protein P15018 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 f Regulation miannu Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway. SIGNOR-251941 0.266 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207239 0.8 SYN1 protein P17600 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269187 0.7 SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.712 IL10 protein P22301 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253496 0.2 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 9606 8006002 t fspada BMP-4 bound to ALK-3 and ALK-6 efficiently SIGNOR-236932 0.852 EZH2 protein Q15910 UNIPROT ALDH1A1 protein P00352 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 f miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. SIGNOR-254141 0.39 OXSR1 protein O95747 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr84 LPSDFEHtIHVGFDA 9606 BTO:0000567 14707132 t miannu OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity. SIGNOR-250210 0.382 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser941 S-->A 9606 BTO:0002181 38307877 t miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  SIGNOR-277917 0.27 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-164 SIGNOR-250014 0.346 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f miannu YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-277640 0.7 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 0.56 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCB protein P05771 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190347 0.8 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 17139329 f fferrentino C/EBPα induces many adipocyte genes directly, and in vivo studies indicate an important role for this factor in the development of adipose tissue. SIGNOR-132946 0.7 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH5 protein P33151 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265845 0.8 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 21666810 t fstefani Like mk2, mk5 could be phosphorylated and activated by p38mapk and erk2 in vitro, but not by sapk?/Jnk3 SIGNOR-174076 0.48 COLGALT2 protein Q8IYK4 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261159 0.452 CALM1 protein P0DP23 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 24379783 t lperfetto Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-251615 0.76 AMP smallmolecule CHEBI:456215 ChEBI MLXIPL protein Q9NP71 UNIPROT down-regulates activity chemical inhibition 10116 26984404 t We discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. SIGNOR-255668 0.8 NF2 protein P35240 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity binding 10090 BTO:0003324 27402866 t Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. SIGNOR-261955 0.327 CXCL10 protein P02778 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 t miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. SIGNOR-260969 0.787 PDPK1 protein O15530 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 t gcesareni We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts. SIGNOR-134866 0.55 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 0.8 RRM1 protein P23921 UNIPROT Ribonucleotide reductase complex SIGNOR-C233 SIGNOR form complex binding 9606 14583450 t miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. SIGNOR-259363 0.933 WWTR1 protein Q9GZV5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 20466877 t gcesareni Taz physically interacts with myod through the ww domain and activates myod-dependent gene transcription. SIGNOR-165414 0.275 chelerythrine chemical CHEBI:78373 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 12702731 t gcesareni Chelerythrine inhibited the bclxl-bak bh3 peptide binding with ic50 of 1.5 micro m and displaced bax, a bh3-containing protein, from bclxl. SIGNOR-100670 0.8 morphine chemical CHEBI:17303 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258765 0.8 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 0.22 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252854 0.911 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. SIGNOR-249048 0.535 NRXN2 protein Q9P2S2 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265460 0.262 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 0.7 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207666 0.8 CROCC protein Q5TZA2 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24035387 t miannu C-Nap1 and rootletin have been previously reported to be the important centrosome linker components involved in centrosome cohesion. SIGNOR-273706 0.7 MYCT1 protein Q8N699 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261731 0.2 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Ser854 HPKPKQFsSFEKRAK 9606 21068236 t lperfetto Phosphorylation of rig-i by casein kinase ii inhibits its antiviral response. Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) SIGNOR-169400 0.2 SLC1A2 protein P43004 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). SIGNOR-264803 0.8 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 0.7 MOB1B protein Q7L9L4 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-169798 0.876 STAT3 protein P40763 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000452 26738736 f miannu Collectively, the activation of IL-6/STAT3 pathway contributed to the PSCs-induced EMT i SIGNOR-277690 0.7 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation 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-260154 0.822 (-)-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 0.8 MAPK8 protein P45983 UNIPROT GRB7 protein Q14451 UNIPROT down-regulates quantity by destabilization phosphorylation Ser194 KYELFKSsPHSLFPE 9606 BTO:0000017 27658202 t miannu Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. I SIGNOR-277280 0.262 TAF10 protein Q12962 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263926 0.897 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 0.619 NR3C1 protein P04150 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9590696 t gcesareni Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP. SIGNOR-251682 0.769 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 SIGNOR-244576 0.2 POLE4 protein Q9NR33 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-265521 0.916 POLR2M protein P0CAP2 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266169 0.453 PTK2B protein Q14289 UNIPROT GSN protein P06396 UNIPROT down-regulates activity phosphorylation 9606 12578912 t miannu Our results demonstrate that PYK2 inhibits this EGTA stable gelsolin-actin monomer association.|PYK2 phosphorylates gelsolin at tyrosine residues and regulates gelsolin bioactivity, including decreasing gelsolin binding to actin monomer and increasing gelsolin binding to phosphatidylinositol lipids. SIGNOR-278325 0.527 EFNA1 protein P20827 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9576626 t gcesareni The best known function is their role in the guidance of migration of axons and cells in the nervous system through repulsive interactions SIGNOR-56965 0.812 MAPK1 protein P28482 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 t miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-262944 0.2 CDK1 protein P06493 UNIPROT FEN1 protein P39748 UNIPROT down-regulates activity phosphorylation Ser187 MDCLTFGsPVLMRHL 9606 BTO:0000007 12853968 t lperfetto Phosphorylation of human fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.As a functional consequence of phosphorylation by cdk1-cyclin a in vitro, endo- and exonuclease activities of fen1 are reduced whereas its dna binding is not affected. SIGNOR-103535 0.446 MC1R protein Q01726 UNIPROT Pigmentation phenotype SIGNOR-PH70 SIGNOR up-regulates 9606 19656324 f miannu Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. SIGNOR-252374 0.7 BMX protein P51813 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity phosphorylation Tyr400 RQGLDEMySDVWKQL 9534 11877430 t miannu Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes. SIGNOR-262679 0.634 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 22863277 t gcesareni Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors. SIGNOR-198526 0.8 SERPINA1 protein P01009 UNIPROT F2 protein P00734 UNIPROT down-regulates activity binding 9606 BTO:0000131 17635716 t lperfetto Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days SIGNOR-263524 0.423 IYD protein Q6PHW0 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267034 0.8 FOXJ1 protein Q92949 UNIPROT DNAH11 protein Q96DT5 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-266931 0.361 CRX protein O43186 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253820 0.47 ID2 protein Q02363 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241149 0.562 g-TuRC complex complex SIGNOR-C282 SIGNOR TUBG1 protein P23258 UNIPROT up-regulates activity binding -1 31862189 t lperfetto Despite its asymmetric architecture, the γ-TuRC arranges γ-tubulins into a helical geometry poised to nucleate microtubules. SIGNOR-262325 0.869 FOXA1 protein P55317 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 19127412 f miannu Overexpression of foxa1 promoted apoptosis SIGNOR-183153 0.7 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity precursor of 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-268085 0.8 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 t miannu The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. SIGNOR-276324 0.256 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 0.8 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 0.916 GYPA protein P02724 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266018 0.366 NOTCH proteinfamily SIGNOR-PF30 SIGNOR ADAM19 protein Q9H013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10933396 f gcesareni Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene. SIGNOR-254340 0.2 GRK2 protein P25098 UNIPROT CXCR2 protein P25025 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000763 22634615 t miannu Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis SIGNOR-260647 0.2 CD79B protein P40259 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268189 0.657 TXNL4A protein P83876 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270638 0.752 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264955 0.7 AP1 complex SIGNOR-C154 SIGNOR SPI1 protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 t miannu 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-260098 0.51 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 0.2 BDKRB1 protein P46663 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256907 0.25 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 0.344 DDIT3 protein P35638 UNIPROT TRIB3 protein Q96RU7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002183 18940792 f miannu Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. SIGNOR-253839 0.573 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT up-regulates activity palmitoylation Cys36 KEKASMLcFKRRKKA 10116 BTO:0004553 25589740 t Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms SIGNOR-262295 0.331 LONP2 protein Q86WA8 UNIPROT TYSND1 protein Q2T9J0 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000567 22002062 t miannu Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. SIGNOR-261054 0.66 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t gcesareni The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells. SIGNOR-197622 0.873 RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. SIGNOR-110917 0.359 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr177 VAGQLTDtMAKRNTV 9534 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues SIGNOR-247573 0.2 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9841871 t lperfetto When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro. SIGNOR-62372 0.657 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 CSNK2A1 protein P68400 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates phosphorylation Ser239 KDSSHYDsDGDKSDD 9606 15367661 t lperfetto These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation. SIGNOR-129026 0.32 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 0.658 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193018 0.8 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263809 0.8 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t gcesareni ...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-249658 0.2 EIF4G2 protein P78344 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity binding 9606 BTO:0000007 29530922 t miannu Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. SIGNOR-266385 0.753 IL17A protein Q16552 UNIPROT KLF3 protein P57682 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-192610 0.2 linifanib chemical CHEBI:91435 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193666 0.8 SMAD2 protein Q15796 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 10090 BTO:0000165 BTO:0001760 SIGNOR-C8 11160896 t lperfetto Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay. SIGNOR-235846 0.39 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 0.455 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser645 LNEKARLsYSDKNLI 10090 BTO:0000944 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248595 0.3 ABL1 protein P00519 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation Tyr425 SDKYGLGyQLCDNSV 9606 27899378 t Manara C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability. SIGNOR-260935 0.29 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 0.2 RIPK3 protein Q9Y572 UNIPROT GLUD1 protein P00367 UNIPROT up-regulates binding 9606 19632174 t gcesareni Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro. SIGNOR-187314 0.446 moclobemide chemical CHEBI:83531 ChEBI MAOA protein P21397 UNIPROT down-regulates activity chemical inhibition -1 21680183 t Luana Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104.  SIGNOR-258314 0.8 UTS2R protein Q9UKP6 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256922 0.25 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 8276865 t gcesareni Lpa activates its own g protein-coupled receptor(s). SIGNOR-36389 0.8 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 0.359 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR up-regulates activity chemical activation 26083061 t lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function SIGNOR-262135 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249352 0.739 SORT1 protein Q99523 UNIPROT APOA1 protein P02647 UNIPROT up-regulates quantity binding 10029 BTO:0000246 23283348 t miannu Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms. SIGNOR-273722 0.331 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-219217 0.552 COX6A1 protein P12074 UNIPROT Cytochrome c oxidase-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-267747 0.732 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. SIGNOR-198544 0.467 panobinostat chemical CHEBI:85990 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257754 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH8 protein P55286 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-265848 0.8 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0000452 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106574 0.766 perfluorododecanoic acid chemical CHEBI:90633 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 t miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. SIGNOR-268759 0.8 PPARGC1A protein Q9UBK2 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 20404331 f lperfetto In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB SIGNOR-217978 0.364 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser813 DIYSRRLsQETGLEI -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-250351 0.485 UBE2I protein P63279 UNIPROT MITF protein O75030 UNIPROT down-regulates ubiquitination Lys308 SEARALAkERQKKDN 9606 10673502 t lperfetto Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo. SIGNOR-75117 0.565 PRKCH protein P24723 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202792 0.2 GZMB protein P10144 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 11081635 t gcesareni The serine proteinase granzyme b is crucial for the rapid induction of target cell apoptosis by cytotoxic t cells. We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (ci-mpr). Inhibition of the granzyme b ci-mpr interaction prevented granzyme b cell surface binding, uptake, and the induction of apoptosis. SIGNOR-84314 0.407 CDK1 protein P06493 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 26352374 t miannu Drp1 is phosphorylated at the Ser616 position and activated predominantly by CDK1. SIGNOR-279394 0.466 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 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-40493 0.332 PLK1 protein P53350 UNIPROT SRI protein P30626 UNIPROT unknown phosphorylation Thr155 YSTNGKItFDDYIAC 9606 24427308 t lperfetto Sorcin interacts physically with plk1, is phosphorylated by plk1 and induces plk1 autophosphorylation, thereby regulating kinase activity. SIGNOR-203732 0.374 PKA proteinfamily SIGNOR-PF17 SIGNOR Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264960 0.7 FOXA1 protein P55317 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19127412 f miannu Foxa1 overexpression decreased the expression of bcl2, while foxa1 depletion increased the expression of bcl2 SIGNOR-161448 0.2 GRIK5 protein Q16478 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264346 0.7 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates transcriptional regulation 9606 23612709 f Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255460 0.509 ACTL6A protein O96019 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270718 0.678 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251168 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation 9606 21419341 t inferred from 70% family members gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. SIGNOR-270161 0.2 MSL1 protein Q68DK7 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271977 0.2 ACSL4 protein O60488 UNIPROT Ferroptosis phenotype SIGNOR-PH234 SIGNOR up-regulates 9606 BTO:0003081 27565726 f miannu Overexpression of ACSL4 promotes ferroptosis SIGNOR-279851 0.7 CCT137690 chemical CID:25154041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190892 0.8 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 0.441 NR3C1 protein P04150 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. SIGNOR-254439 0.282 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates activity chemical inhibition -1 23515850 t lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro SIGNOR-262023 0.8 NEDD4 protein P46934 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 25088038 t miannu NEDD4 promotes MDM2 ubiquitination in a dose- and time-dependent manner, whereas depletion of NEDD4 reduced the half-life of endogenous MDM2 [ xref ]. SIGNOR-278769 0.466 ASTN1 protein O14525 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28506896 f miannu The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development SIGNOR-269815 0.7 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 0.46 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 0.8 CDK5 protein Q00535 UNIPROT DRD2 protein P14416 UNIPROT down-regulates activity phosphorylation Ser321 GLHSTPDsPAKPEKN 9606 24391960 t miannu These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling. SIGNOR-259401 0.383 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 0.39 CPE protein P16870 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates activity cleavage 9606 25767437 t miannu First, OT preprohormone is produced, that will be cleaved and matured by successive enzymes. The OT gene encodes for the Pre-Pro-OT-Neurophysin I (pre-pro-hormone), which is cleaved by different enzymes to give rise to different OT intermediate forms and to the Neurophysin I, and finally to the mature amidated form that is released (Figure ​2). SIGNOR-270338 0.2 CPT1A protein P50416 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267126 0.8 ALS2 protein Q96Q42 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity binding 9606 BTO:0000567 30485418 t miannu ALS2 activates Rab5 on macropinosomes. Rab5 is activated and concurrently recruited to macropinosomes during ruffle closure. ALS2 depletion abolishes transient Rab5 activation on macropinosomes, while ALS2 is recruited to macropinosomes simultaneously with Rab5 activation. Thus, we conclude ALS2 activates Rab5 on macropinosomes. SIGNOR-277776 0.735 B-WICH complex complex SIGNOR-C447 SIGNOR MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0000567 25883140 t miannu The B-WICH complex allows c-Myc to bind to a site in the IGS. c-Myc requires the B-WICH complex to remodel chromatin for its function. SIGNOR-268842 0.295 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1222 ESSSTRRsSEDLSAY 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-236729 0.2 GPR132 protein Q9UNW8 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-257444 0.402 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270424 0.8 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 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr564 LEEADNQtLDSYRNE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276215 0.2 NONO protein Q15233 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 BTO:0000017 9756848 t miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i SIGNOR-60557 0.373 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 0.855 CALM2 protein P0DP24 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-266325 0.2 ABL1 protein P00519 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr52 LTRDETNyGIPQRAL 9606 19423701 t lperfetto Phosphorylation of rack1 on tyrosine 52 by c-abl is required for insulin-like growth factor i-mediated regulation of focal adhesion kinase.Tyrosine 52 is further shown to be phosphorylated by c-abl kinase, and the c-abl inhibitor sti571 disrupts fak interaction with rack1 SIGNOR-185649 0.2 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD9 protein O15198 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-270211 0.2 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 0.929 SMAD1 protein Q15797 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-268938 0.291 ALDOB protein P05062 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266488 0.8 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201274 0.609 GSK3A protein P49840 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 t gcesareni Similar to c-myc, 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-138596 0.406 MAPK11 protein Q15759 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser113 STSVTPHsPSSPVGS 9606 BTO:0000007 16713578 t miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles SIGNOR-262946 0.264 RPS6KB1 protein P23443 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 17181399 f gcesareni Finally, downregulation of p70 s6 kinase by sirna significantly enhanced the fgf-2-stimulated vegf release and phosphorylation of sapk/jnk. SIGNOR-149367 0.42 PTCH1 protein Q13635 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-209602 0.585 PRKAA2 protein P54646 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-250158 0.498 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 0.351 USP7 protein Q93009 UNIPROT DEPTOR protein Q8TB45 UNIPROT up-regulates quantity by stabilization deubiquitination -1 35216969 t miannu Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay. SIGNOR-277588 0.2 GAB1 protein Q13480 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 t gcesareni Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2. SIGNOR-102586 0.314 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT -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-250087 0.525 HSP90AA1 protein P07900 UNIPROT FER protein P16591 UNIPROT down-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ 9606 BTO:0002181 19159681 t miannu Hsp90 and tyrosine616 are required for Fer tyrosine kinase activity.Taken together, our findings underscore the importance of Hsp90 and the residue, tyrosine616, which resides in the Hsp90 recognition loop, in maintaining Fer tyrosine kinase activity. SIGNOR-277818 0.3 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 0.636 CDK1 protein P06493 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser394 SKDAKVPsPPPGHKW -1 18408216 t miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. SIGNOR-276157 0.349 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 11208622 t ashma gcesareni SIGNOR-251687 0.8 RNF139 protein Q8WU17 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  SIGNOR-271957 0.298 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 0.9 POMC protein P01189 UNIPROT 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-258409 0.65 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-26211 0.788 AGO2 protein Q9UKV8 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 t miannu SIGNOR-143102 0.814 PIM1 protein P11309 UNIPROT RP9 protein Q8TA86 UNIPROT unknown phosphorylation Ser214 RKHKSSKsNEGSDSE -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-263030 0.2 CNOT6L protein Q96LI5 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-268311 0.813 FOXO1 protein Q12778 UNIPROT FSHB protein P01225 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004467 24065703 f miannu We demonstrate that FOXO1 represses basal and GnRH-induced Fshb transcription in LβT2 cells. SIGNOR-254185 0.346 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10037602 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-64968 0.858 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser139 YFLGSSFsPVRCGGP 9606 23051732 t lperfetto However, when both Ser 123 and Ser 139 were modified (2A), although Wee1 was still phosphorylated by Cdk1, treatment with active Cdc14A did not decrease the phosphorylation signal to any significant extent (XREF_FIG, lane 5), indicating that Cdc14A dephosphorylates Wee1 at Ser 123 and Ser 139 residues.|Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity. SIGNOR-276953 0.545 ITGB1BP1 protein O14713 UNIPROT A8/b1 integrin complex SIGNOR-C165 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-257645 0.732 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 0.285 CASP7 protein P55210 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261746 0.318 BRCA1 protein P38398 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 15549093 f lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination SIGNOR-251500 0.7 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000142 10226025 t acerquone We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies. SIGNOR-67367 0.748 ME1 protein P48163 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 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-267717 0.8 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 0.2 TMLHE protein Q9NVH6 UNIPROT N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:17311 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-269681 0.8 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 0.245 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 0.906 BLOC1S1 protein P78537 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-265936 0.731 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 0.2 SP1 protein P08047 UNIPROT GFER protein P55789 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18513187 f miannu We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1. SIGNOR-254450 0.2 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 0.531 ADSS2 protein P30520 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 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-267345 0.8 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 0.8 PRKCB protein P05771 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-249183 0.398 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation 9606 32827753 t miannu Cdk4 phosphorylation on GCN5 augments the acetyltransferase catalytic activity of GCN5, by increasing maximal velocity (V ), whereas the Michaelis-Menten constant for Acetyl-CoA binding was unaffected.|Cdk4 phosphorylation on GCN5 augments the acetyltransferase catalytic activity of GCN5, by increasing maximal velocity (V max ), whereas the Michaelis-Menten constant for Acetyl-CoA binding was unaffected. SIGNOR-279018 0.36 EPC1 protein Q9H2F5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269305 0.661 caffeine chemical CHEBI:27732 ChEBI PDE2A protein O00408 UNIPROT down-regulates activity chemical inhibition 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-275729 0.8 PRKCQ protein Q04759 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 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-249256 0.303 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 0.8 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr846 DGGGSDRyGSLRPGW 9606 BTO:0000763 20861316 t lperfetto Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity SIGNOR-168001 0.3 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191133 0.8 FANCC protein Q00597 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-263246 0.923 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 0.8 EEF1D protein P29692 UNIPROT ITGA7 protein Q13683 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 16129691 t lperfetto alpha7 Integrin Expression Is Negatively Regulated by deltaEF1 during Skeletal Myogenesis SIGNOR-241773 0.2 CHD8 protein Q9HCK8 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR up-regulates activity binding 9606 BTO:0000946 20085832 t miannu Chromodomain, helicase, DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin remodeling enzyme that has been demonstrated to exist within a large protein complex which includes WDR5, Ash2L, and RbBP5, members of the Mixed Lineage Leukemia (MLL) histone modifying complexes. CHD8 forms a complex with the core WDR5/Ash2L/RbBP5 complex. CHD8 is required for recruitment of the WAR complex SIGNOR-268807 0.429 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268204 0.8 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-121994 0.475 1-(4,4-diphenylbut-3-enyl)-3-piperidinecarboxylic acid chemical CHEBI:91734 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-258478 0.8 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 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-157742 0.868 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250932 0.307 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4C protein Q08493 UNIPROT up-regulates activity phosphorylation Ser14 GEGAEACsRLSRSRG 9534 12023945 t miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. SIGNOR-273938 0.2 XL147 chemical CHEBI:71957 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207854 0.8 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 0.599 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 0.7 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 0.399 PTPN2 protein P17706 UNIPROT STAT5B protein P51692 UNIPROT down-regulates activity dephosphorylation 9606 12359225 t miannu In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway. SIGNOR-277126 0.733 SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 t gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 0.712 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 0.468 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 0.625 AMPK complex SIGNOR-C15 SIGNOR SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation Ser555 AEGERRGsLAFIRSP 9606 BTO:0000195 38047302 t miannu AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563. SIGNOR-277849 0.2 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 0.276 glycine smallmolecule CHEBI:15428 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 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-264985 0.8 NAE1 protein Q13564 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway SIGNOR-251579 0.7 GSK3B protein P49841 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser270 KMALTKAsSVASSDK 9606 BTO:0002181 27432879 t miannu Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser274 SIGNOR-277244 0.285 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 t gcesareni We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta. SIGNOR-139870 0.2 SGK1 protein O00141 UNIPROT WNK4 protein Q96J92 UNIPROT up-regulates activity phosphorylation Ser1201 FPTSRRNsLQRSEPP -1 23054253 t miannu In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM. SIGNOR-276421 0.415 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. SIGNOR-178190 0.681 CENPC protein Q03188 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265200 0.664 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni Flt3 is activated by binding of its natural flt3-ligand (flt3-l), SIGNOR-99750 0.885 RUNX3 protein Q13761 UNIPROT DNASE1 protein P24855 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-255092 0.2 Protocadherin_alpha proteinfamily SIGNOR-PF100 SIGNOR Protocadherin_beta proteinfamily SIGNOR-PF102 SIGNOR up-regulates activity binding 9606 BTO:0000007 15347688 t miannu We analyzed the expression of CNR/Pcdhalpha and Pcdhgamma in HEK293T cells and found that they formed a protein complex and that Pcdhgamma enhanced the surface expression of CNR/Pcdhalpha. This enhanced surface expression was confirmed by flow cytometry analysis and by marking cell surface proteins with biotin. The enhancement was observed using different combinations of CNR/Pcdhalpha and Pcdhgamma proteins. The surface expression activity was enhanced by the extracellular domains of the proteins, which could bind each other. Their cytoplasmic domains also had binding activity and influenced their localization. Their protein-protein interaction was also detected in extracts of mouse brain and two neuroblastoma cell lines. Thus, interactions between CNR/Pcdhalpha and Pcdhgamma regulate their surface expression and contribute to the combinatorial diversity of cell recognition proteins in the brain. SIGNOR-269036 0.2 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 0.406 CDK1 protein P06493 UNIPROT RFC1 protein P35251 UNIPROT down-regulates activity phosphorylation Thr506 KESKLERtPQKNVQG 9534 BTO:0004055 12930972 t lperfetto Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. |Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA. SIGNOR-265504 0.245 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 0.284 SP2 protein Q02086 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001677 10744779 t Luana Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells. SIGNOR-266230 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t lperfetto Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis. SIGNOR-244373 0.2 TRIM58 protein Q8NG06 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys172 ENWPKTLkLALEKER 23499489 t lperfetto Specifically, the ubiquitin E3 ligase TRIM25 ubiquitinates K172 in the CARD2 of RIG-I, which is essential for the efficient interaction of RIG-I with MAVS and thereby for antiviral signal transduction  SIGNOR-264582 0.2 RALGDS protein Q12967 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220923 0.497 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 f lperfetto Ribosomes are translational machineries that catalyse protein synthesis. SIGNOR-262412 0.7 SIRT7 protein Q9NRC8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275886 0.2 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 19958286 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-161929 0.619 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TH protein P07101 UNIPROT up-regulates phosphorylation 9606 7901013 t inferred from 70% family members gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 SIGNOR-270167 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC7 protein O00311 UNIPROT up-regulates activity phosphorylation Thr376 QVAPRAGtPGFRAPE -1 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-250643 0.468 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 0.2 AMG-208 chemical CHEBI:90626 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189507 0.8 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser126 NPEAESSsKEGELDA -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276115 0.711 dexamethasone chemical CHEBI:41879 ChEBI GLUL protein P15104 UNIPROT up-regulates quantity by expression 10090 8099704 f miannu GS transcripts were measured by laser densitometry and normalized to actin, and GS specific activity was also determined. Following a single injection of dexamethasone (0.5 mg/kg), lung GS activity increased by 40% at 4 hours and by 75% at 8 hours. The dexamethasone-mediated increase in GS activity was associated with a marked increase in GS mRNA levels, which preceded the increase in enzyme activity by approximately 2 hours. SIGNOR-267827 0.8 GUCY1B1 protein Q02153 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243986 0.2 SKI protein P12755 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 12419246 t gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5. SIGNOR-195630 0.699 TP53 protein P04637 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255434 0.363 PPARGC1A protein Q9UBK2 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 20640476 f Gianni However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis SIGNOR-209932 0.7 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 0.2 FBXW7 protein Q969H0 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 24820417 t miannu Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.  SIGNOR-276635 0.403 CAPN1 protein P07384 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251586 0.297 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 0.266 ZHX1 protein Q9UKY1 UNIPROT ZMYND11 protein Q15326 UNIPROT down-regulates activity binding 9606 BTO:0000007 17127430 t miannu Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1. SIGNOR-263898 0.491 STUB1 protein Q9UNE7 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates quantity by destabilization ubiquitination Lys284 WFCNRRQkGKRSSSD 9606 29511337 t miannu CHIP overexpression decreased OCT4 stability through proteasomal degradation.|CHIP E3 ligase ubiquitinates OCT4 at lysine 284.|These data suggest that CHIP induces OCT4 ubiquitination and degradation. SIGNOR-278562 0.303 RAMAC protein Q9BTL3 UNIPROT RNMT protein O43148 UNIPROT up-regulates activity binding 9606 27422871 t lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. SIGNOR-268344 0.2 STUB1 protein Q9UNE7 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25879443 t miannu Our results indicate that the post-endocytic ubiquitination of CFTR by CHIP is a critical step in the peripheral quality control of cell surface DeltaF508 CFTR. SIGNOR-278668 0.471 NEURL1 protein O76050 UNIPROT JAG1 protein P78504 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26276215 t miannu We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.|Jagged1 is also regulated by the E3 ligase Neuralized-like1 (Neurl1), which induces the monoubiquitination of membrane tethered Jagged1 in the C-terminal region. SIGNOR-278772 0.707 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 0.404 TOP2B protein Q02880 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 24463367 f lperfetto Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells SIGNOR-242533 0.7 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 0.7 PATZ1 protein Q9HBE1 UNIPROT RNF4 protein P78317 UNIPROT down-regulates binding 9606 10713105 t miannu In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression SIGNOR-75775 0.511 ULK3 protein Q6PHR2 UNIPROT GLI2 protein P10070 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-260798 0.621 NAE1 protein Q13564 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway SIGNOR-256651 0.7 NOTCH1 protein P46531 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 19165418 t gcesareni The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j. SIGNOR-183510 0.95 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 0.8 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC3 protein Q9UN70 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265674 0.2 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 9606 15843801 f gcesareni We have identified a new cell population that expresses the transcription factors pax3 and pax7 (paired box proteins 3 and 7) but no skeletal-muscle-specific markers. SIGNOR-135626 0.7 DIP2A protein Q14689 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity binding 10090 BTO:0000142 33781892 t miannu DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. SIGNOR-266591 0.2 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates 9606 8069916 f gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-33843 0.72 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 0.8 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr25 APPPQPPtPALPHPP 9606 8846784 t lperfetto Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation SIGNOR-44351 0.769 AKT2 protein P31751 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates 9606 17604717 f gcesareni Several studies have demonstrated that akt signaling can activate the nf-kb transcription factor downstream of a variety of stimuli, such as tumor necrosis factor (tnfalfa) SIGNOR-156530 0.329 HTR1B protein P28222 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257115 0.25 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 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-159429 0.2 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 0.7 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194560 0.8 iron(3+) smallmolecule CHEBI:29034 ChEBI SLC40A1 protein Q9NP59 UNIPROT down-regulates quantity relocalization 9606 39534872 t miannu Fe3+ is taken up by TFRC and exported by SLC40A1. Inside the cell, Fe3+ is reduced to Fe2+, with excess iron stored in ferritin (composed of FTH1 and FTL) or sequestered by MT1G. SIGNOR-279857 0.8 CCT239065 chemical CID:44131523 PUBCHEM LCK protein P06239 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190910 0.8 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 0.66 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 0.606 EEF1A2 protein Q05639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269536 0.8 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 0.282 NEFH protein P12036 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 f miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. SIGNOR-252390 0.7 PPM1B protein O75688 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 25631048 t PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation SIGNOR-251712 0.2 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 0.31 DAB2IP protein Q5VWQ8 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR up-regulates activity binding 9606 20080667 t miannu DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation SIGNOR-254753 0.2 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 0.248 PARD6/SMURF1 complex SIGNOR-C112 SIGNOR RHOA protein P61586 UNIPROT down-regulates ubiquitination 9606 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-227492 0.675 MAP2 protein P11137 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000938 10704996 t lperfetto MAP2 interacts with MTs through its tubulin-binding domain which mainly associates with the acidic region of the C-terminal region of tubulin|no neurite growth is observed when MAP2 expression is suppressed in neuronal cell cultures after treatment with specific antisense oligonucleotides SIGNOR-264837 0.7 PDE4DIP protein Q5VU43 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates binding 9606 21569246 t miannu Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a. SIGNOR-173769 0.315 SRT1720 chemical CID:25232708 PUBCHEM SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation 9606 18046409 t Selleck gcesareni Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. SIGNOR-207114 0.8 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 0.744 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257964 0.8 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 0.257 AKT proteinfamily SIGNOR-PF24 SIGNOR CCNF protein P41002 UNIPROT up-regulates activity phosphorylation Thr31 RRRPRNLtILSLPED 9606 BTO:0001938 28954236 t miannu AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. SIGNOR-266360 0.2 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 t milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 0.8 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 0.8 MMP11 protein P24347 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272379 0.7 LCK protein P06239 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates phosphorylation Tyr342 NMRPPFTyATLIRWA 9606 24155921 t llicata Lck phosphorylated tyr-342 of foxp3 by immunoprecipitation and in vitro kinase assay, and the replacement of tyr-342 with phenylalanine (y342f) abolished the ability to suppress mmp9 expression. SIGNOR-203089 0.401 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 0.646 MAP1LC3B protein Q9GZQ8 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 20921139 f lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation SIGNOR-219403 0.7 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 0.7 GNA12 protein Q03113 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity binding 101841 BTO:0000298 12176367 t Marta Tosoni In this study, we show that active forms of Gna12 and Gna13 specifically interact with PP5 through its TPR domain and activate its phosphatase activity about 2.5-fold. SIGNOR-278080 0.326 GNA13 protein Q14344 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity binding 101841 BTO:0000298 12176367 t Marta Tosoni In this study, we show that active forms of G12 and G13 specifically interact with PP5 through its TPR domain and activate its phosphatase activity about 2.5-fold. Active forms of G12 and G13 also enhance the arachidonic acid-stimulated PP5 phosphatase activity about 2.5-fold. SIGNOR-278081 0.326 GNA12 protein Q03113 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity binding 9606 BTO:0000007 9796816 t Marta Tosoni Here we show that Ga12 binds directly to, and stimulates the activity of, Bruton’s tyrosine kinase (Btk) and a Ras GTPase-activating protein, Gap1m, in vitro and in vivo SIGNOR-278082 0.317 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 0.8 CAMK4 protein Q16566 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates phosphorylation Ser91 RARPRKIsSPTGSKD 9606 BTO:0000887 21689744 t lperfetto Here we show that calcium/calmodulin-dependent kinase iv (camk iv) specifically binds to the c terminus of phb2 and phosphorylates phb2 at serine 91. Camk iv effectively decreased phb2-mediated repression of mef2 activity through phosphorylation SIGNOR-174437 0.338 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser748 DSEGFEDsFEEEEEE 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265271 0.291 PIM1 protein P11309 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 t llicata In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276. SIGNOR-189125 0.2 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 BTO:0001538 10748061 t miannu That phosphorylation of serines 77 and 79 by cdk7 could be responsible for efficient transcription was further supported by the observation that overexpressed cdk7 significantly enhanced transcription by hRARγ1WT but not by hRARγ1S77A/S79A (Fig. 9 B).  SIGNOR-277896 0.418 ABL1 protein P00519 UNIPROT VCL protein P18206 UNIPROT up-regulates activity phosphorylation Tyr822 KSFLDSGyRILGAVA 9606 24751539 t miannu Abl is the tyrosine kinase that phosphorylates vinculin Y822.|Finally we show that Abl inhibition prevents vinculin actions in cadherin containing complexes, resulting in defects in cell stiffening. SIGNOR-278464 0.38 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 0.347 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 0.2 CDH9 protein Q9ULB4 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-265871 0.586 PPARA protein Q07869 UNIPROT PLIN2 protein Q99541 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 f miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. SIGNOR-255046 0.547 ASMT protein P46597 UNIPROT melatonin smallmolecule CHEBI:16796 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-265475 0.8 UBE3A protein Q05086 UNIPROT MCM7 protein P33993 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 9852095 t miannu The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome. SIGNOR-272543 0.401 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 0.2 YAP1 protein P46937 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 30348863 f lperfetto Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. SIGNOR-276584 0.26 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 t milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 0.8 WWTR1 protein Q9GZV5 UNIPROT PAX3 protein P23760 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 16300735 t gcesareni These results indicate that pax3 specifically interacts with taz both in vitro and in vivo. SIGNOR-236879 0.454 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 0.2 tyrosine smallmolecule CHEBI:18186 ChEBI L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). SIGNOR-264173 0.8 alvocidib chemical CHEBI:47344 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191529 0.8 ITGB6 protein P18564 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257724 0.49 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22469984 t irozzo The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a SIGNOR-259360 0.338 torin 2 chemical CHEBI:90682 ChEBI RPS6KB1 protein P23443 UNIPROT down-regulates 9606 23436801 f gcesareni Torin2 inhibited mtorc1-dependent t389 phosphorylation on s6k (rps6kb1) SIGNOR-201502 0.8 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 0.8 ER stress stimulus SIGNOR-ST9 SIGNOR BID protein P55957 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196944 0.7 GPER1 protein Q99527 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000130 22203955 t gcesareni However, grpr preferentially couples to galfaq proteins. SIGNOR-195320 0.2 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267080 0.8 SLC34A1 protein Q06495 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 20335586 t lperfetto Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, SIGNOR-270576 0.8 CDK5 protein Q00535 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates quantity phosphorylation Ser75 RQAFQIGsPWRTMDA 9606 29948941 t miannu Cdk5 Phosphorylates ALDH1A1 at S75 and S274.|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites. SIGNOR-279400 0.2 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 0.943 PKA proteinfamily SIGNOR-PF17 SIGNOR VASP protein P50552 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268286 0.2 BMPR1B protein O00238 UNIPROT SMAD9 protein O15198 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-255264 0.708 ATR protein Q13535 UNIPROT PALB2 protein Q86YC2 UNIPROT up-regulates activity phosphorylation 9606 28089683 t miannu ATR promotes PALB2 accumulation at DNA damage sites.|In the context of PALB2 regulation, the phosphorylation of PALB2 by ATR plays a positive role in PALB2 recruitment. SIGNOR-279588 0.307 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 11369754 t lperfetto These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108257 0.455 CDK8 protein P49336 UNIPROT MED13 protein Q9UHV7 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 29212878 t miannu Here, cyclin C-Cdk8 phosphorylation of Med13 most likely primes the phosphodegron for destruction. SIGNOR-279687 0.901 PAK1 protein Q13153 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma. SIGNOR-48673 0.2 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCE protein Q02156 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191496 0.8 PPP2CA protein P67775 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates dephosphorylation 9606 20626350 t lperfetto 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-244941 0.559 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265112 0.8 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 0.493 TP53INP1 protein Q96A56 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22421968 t gcesareni Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir). SIGNOR-196670 0.348 Caspase 7 complex complex SIGNOR-C232 SIGNOR PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 t amattioni Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis. SIGNOR-256470 0.719 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34657 0.601 F2R protein P25116 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 22318735 t gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). SIGNOR-196009 0.402 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 0.226 AKT1 protein P31749 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity 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-79335 0.552 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR PECAM1 protein P16284 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The platelet endothelial cell adhesion molecule PECAM1 is also downregulated by NUP98‐HOXA9. SIGNOR-261500 0.2 NEK2 protein P51955 UNIPROT CDC20 protein Q12834 UNIPROT up-regulates activity phosphorylation 9606 20034488 t miannu In summary, we have demonstrated that Nek2 can associate with and phosphorylate Mad2 and Cdc20.|The results presented here support a model in which Nek2 modulates the functions of Mad2 and Cdc20 in the mitotic checkpoint and elevation of Nek2 levels may contribute to chromosome instability by interfering with the control of the checkpoint. SIGNOR-278366 0.945 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 0.664 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 1159081 t inflammation gcesareni SIGNOR-251697 0.8 BRCA1 protein P38398 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 15549093 f lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination SIGNOR-267282 0.7 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 0.546 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 t lperfetto IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes SIGNOR-249531 0.765 PD318088 chemical CID:10231331 PUBCHEM MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205737 0.8 PTPN13 protein Q12923 UNIPROT EFNB1 protein P98172 UNIPROT up-regulates activity dephosphorylation 9606 23811940 t lperfetto Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals. SIGNOR-277002 0.708 regorafenib chemical CHEBI:68647 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206418 0.8 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, 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-134219 0.917 olaparib chemical CHEBI:83766 ChEBI PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195019 0.8 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser11 KTKRTADsSSSEDEE 9606 21245376 t gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. SIGNOR-171695 0.368 CDK1 protein P06493 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1. SIGNOR-252890 0.511 EGFR protein P00533 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr136 GDCCYEEyKDRKREN 9606 BTO:0000007 22198508 t miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. SIGNOR-276397 0.2 HCRT protein O43612 UNIPROT HCRTR2 protein O43614 UNIPROT up-regulates binding 9606 9491897 t gcesareni Identification and initial biological characterization of two orexins as well as their two receptors SIGNOR-55848 0.776 RCAN1 protein P53805 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR down-regulates activity binding 9606 12554096 t MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure SIGNOR-252341 0.605 BTRC protein Q9Y297 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 t gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. SIGNOR-64496 0.825 GLI2 protein P10070 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates quantity transcriptional regulation 9606 NBK6142 f SimoneGraziosi Therefore, Gli2 activity regulates the late phase of Olig2 gene expression in the ventral neuroepithelium and its subsequent production of OPC cells. SIGNOR-269219 0.354 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 0.8 CLOCK protein O15516 UNIPROT PER2 protein O15055 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-253634 0.777 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 0.46 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 0.571 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 0.599 coenzyme Q10 smallmolecule CHEBI:46245 ChEBI ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity precursor of 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-267429 0.8 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2. SIGNOR-96952 0.31 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t lperfetto Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro. SIGNOR-114094 0.2 MEF2D protein Q14814 UNIPROT MYH10 protein P35580 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-238766 0.322 SP1 protein P08047 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9148896 f lperfetto These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport. SIGNOR-241485 0.358 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 0.27 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 0.662 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr751 SKDESVDyVPMLDMK 9606 18567737 t gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. SIGNOR-179076 0.691 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser111 KESLRSRsTRMSTVS 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-155894 0.731 TWIST1 protein Q15672 UNIPROT CSNK2A1 protein P68400 UNIPROT down-regulates 9606 22975381 f amattioni Ck2-mediated phosphorylation at ser392 of p53 was attenuated in the presence of recombinant twist1 SIGNOR-192064 0.2 LRRK2 protein Q5S007 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 9606 28553204 t miannu LRRK2 Directly Phosphorylates RCAN1. SIGNOR-278340 0.371 SNARE_complex complex SIGNOR-C346 SIGNOR Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 30267828 f miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-265065 0.7 DCC protein P43146 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 BTO:0001484 25881791 f miannu DCC constitutively expresses on the axonal surface. Netrin-1-binding to DCC induces chemoattraction SIGNOR-268163 0.7 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. SIGNOR-249140 0.308 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 SIGNOR-C3 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-154810 0.926 E2F1 protein Q01094 UNIPROT MT1G protein P13640 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000394 15735762 f lperfetto The E2F transcription factors induce the expression of many genes in response to specific extracellular stimuli. Here, we show that human metallothionein 1G (hMT1G) promoter is upregulated by E2F1 upon VEGF stimulation of human aortic endothelial cells. SIGNOR-254132 0.332 IL1R1 protein P14778 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto The Il-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. SIGNOR-171876 0.7 CYC-116 chemical CID:6420138 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191224 0.8 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 t lperfetto C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1 SIGNOR-86017 0.385 CDC20 protein Q12834 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity binding 9606 BTO:0000567 19822757 t lperfetto Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity SIGNOR-265082 0.872 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT up-regulates activity phosphorylation Tyr136 EDDDANSyENVLICK 10090 BTO:0001930 14722116 t miannu Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases. SIGNOR-273576 0.592 TBK1 protein Q9UHD2 UNIPROT NUMA1 protein Q14980 UNIPROT up-regulates activity phosphorylation 9606 26656453 t miannu Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells. SIGNOR-278432 0.2 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 11175253 t Translocation from Mitochondria to Cytosol amattioni Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux SIGNOR-105206 0.566 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001332 19903340 f lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression SIGNOR-244439 0.634 MAPK8 protein P45983 UNIPROT DCX protein O43602 UNIPROT up-regulates activity phosphorylation 9606 21477071 t miannu DCX phosphorylation by JNK1 is required for glioma suppression. SIGNOR-279217 0.286 NFATC1 protein O95644 UNIPROT IL2 protein P60568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10022916 t Barakat Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses. SIGNOR-275405 0.565 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 0.2 AMG 900 chemical CID:24856041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189498 0.8 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 0.847 E2F1 protein Q01094 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22832221 f gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. SIGNOR-198470 0.679 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates activity binding 9606 BTO:0000567 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-80218 0.914 ketanserin chemical CHEBI:6123 ChEBI SLC18A1 protein P54219 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-258493 0.8 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 0.48 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser176 ERLKKMLsEGSVGEV -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-262686 0.2 MYOD1 protein P15172 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates binding 9606 15870273 t lperfetto This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion SIGNOR-136130 0.538 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 t milica This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain. SIGNOR-163548 0.914 PJA2 protein O43164 UNIPROT PRKAR1B protein P31321 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-271857 0.2 NTRK1 protein P04629 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates binding 9606 BTO:0000938 15082760 t lperfetto The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons. SIGNOR-124198 0.54 PP121 chemical CHEBI:50915 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206295 0.8 (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 0.8 AVP protein P01185 UNIPROT BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 BTO:0000142 18402937 f gcesareni Vp induces phosphorylation of the pro-apoptotic protein bad and prevents cytochrome c release. SIGNOR-178197 0.2 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191094 0.8 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207669 0.8 ULK2 protein Q8IYT8 UNIPROT PRKAB1 protein Q9Y478 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity SIGNOR-173092 0.329 MK-2461 chemical CID:44137946 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194367 0.8 QRICH1 protein Q2TAL8 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 33384352 f miannu QRICH1 promotes cell death and its translation is upregulated by the PERK-eIF2α axis under ER stress. SIGNOR-269399 0.7 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190149 0.8 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194257 0.8 WAY-600 chemical CID:25229526 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor mTOR gcesareni SIGNOR-207788 0.8 CRP protein P02741 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18708524 f Regulation of expression miannu C-reactive protein enhances macrophage lipoprotein lipase expression. SIGNOR-251852 0.371 ERBB4 protein Q15303 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146888 0.319 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192038 0.8 ezogabine chemical CHEBI:68584 ChEBI KCNQ2 protein O43526 UNIPROT up-regulates chemical activation 9606 Other t Selleck;anticonvulsant for KCNQ2/3 currents gcesareni SIGNOR-206483 0.8 PIDD1 protein Q9HB75 UNIPROT Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR form complex binding 9606 20158568 t miannu The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. SIGNOR-262643 0.85 CASP3 protein P42574 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-66863 0.7 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252652 0.8 UBAP2 protein Q5T6F2 UNIPROT ANXA2 protein P07355 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0002181 27121050 t Sara UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination SIGNOR-261314 0.341 Elongator complex complex SIGNOR-C466 SIGNOR TUBA8 protein Q9NY65 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269721 0.252 PHA-848125 chemical CID:16718576 PUBCHEM CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206148 0.8 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192780 0.8 DUSP4 protein Q13115 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 16849326 t gcesareni This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38 SIGNOR-147958 0.665 GW 3965 chemical CHEBI:79995 ChEBI NR1H3 protein Q13133 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-193015 0.8 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11404076 t gcesareni We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins SIGNOR-108499 0.601 rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 7768881 t An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) SIGNOR-251646 0.8 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 12167711 t gcesareni Hypophosphorylation of mdm2 augments p53 stability. SIGNOR-91195 0.345 ADIPOR1 protein Q96A54 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 16622416 t milica Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. SIGNOR-146212 0.751 NODAL protein Q96S42 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0004094 15531507 f Regulation miannu Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. SIGNOR-251935 0.7 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 9606 27563484 f ggiuliani Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression. SIGNOR-255836 0.595 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A12 protein P48065 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207031 0.8 PHA-767491 chemical CID:11715767 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206112 0.8 PF-03814735 chemical CID:49830590 PUBCHEM PTK2 protein Q05397 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205959 0.8 NOD2 protein Q9HC29 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 f miannu Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase. SIGNOR-252412 0.37 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 23583303 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-201687 0.475 SP6 protein Q3SY56 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression transcriptional regulation 19088080 f lperfetto Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. SIGNOR-271695 0.308 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194563 0.8 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 9606 21808241 t inferred from 70% family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-270218 0.2 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 t milica Both il-4 and il-13 use the IL-4R Chain as a component of their receptors. SIGNOR-100753 0.896 SOX2 protein P48431 UNIPROT NR2E1 protein Q9Y466 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22194602 f miannu Sox2 positively regulates tlx expression SIGNOR-191714 0.374 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205942 0.8 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10812968 t amattioni Signal transduction by cntf requires that it bind first to cntfr alpha. Cntf activates downstream signaling molecules SIGNOR-77408 0.791 TRPC6 protein Q9Y210 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates activity 9606 27383564 f gcesareni TRPC6 channel-dependent [Ca2+]i elevation and sequential activation of the calcineurin. SIGNOR-253328 0.2 AMOTL2 protein Q9Y2J4 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0001176 21937427 f lperfetto Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells. SIGNOR-271872 0.7 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12393875 t gcesareni Lpa-induced rac activation requires tiam1 SIGNOR-94691 0.75 FOS protein P01100 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 10090 2516828 t The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities. SIGNOR-252087 0.953 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh. SIGNOR-255891 0.2 GTF3C6 protein Q969F1 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266183 0.868 MIB1 protein Q86YT6 UNIPROT DLL3 protein Q9NYJ7 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209672 0.35 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268016 0.7 GNAI3 protein P08754 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 t TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation SIGNOR-256490 0.2 seliciclib chemical CHEBI:45307 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206568 0.8 NFIL3 protein Q16649 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 10090 BTO:0003104 10082541 f lperfetto the effect of NFIL3 on cytokine-mediated cell survival was independent of an effect on cell proliferation. SIGNOR-242760 0.7 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 9804834 t llicata Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha SIGNOR-250966 0.595 Telatinib chemical CID:9808844 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207221 0.8 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI BMPR1A protein P36894 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193642 0.8 MTX1 protein Q13505 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 t lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. SIGNOR-267684 0.697 GSK1059615 chemical CHEBI:71955 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192693 0.8 RHEB protein Q15382 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding -1 25660019 t Luana Rheb GTPase directly binds and activates PERK in vitro SIGNOR-260873 0.2 HIP1 protein O00291 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11007801 f miannu Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. SIGNOR-256646 0.7 TNFAIP3 protein P21580 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 18164316 t lperfetto A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6 SIGNOR-160223 0.702 CENPE protein Q02224 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity 10090 BTO:0000452 12925705 f lperfetto CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores SIGNOR-252044 0.636 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates chemical inhibition 9606 19759537 t gcesareni Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2. SIGNOR-188054 0.8 RASSF5 protein Q8WWW0 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A SIGNOR-249587 0.543 TGFB1 protein P01137 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 19114990 t lperfetto While association of the TGF_RI receptor with p85 requires TGF-_ stimulation. SIGNOR-217960 0.258 3-(3-oxo-1H-indol-2-ylidene)-1H-indol-2-one chemical CHEBI:92322 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193402 0.8 IGF1R protein P08069 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 10471495 t flangone Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway. SIGNOR-70477 0.802 TGFB1 protein P01137 UNIPROT RNF111 protein Q6ZNA4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14657019 f lpetrilli Expression of arkadia is down-regulated by tgf-beta. SIGNOR-119669 0.2 IL1A protein P01583 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto Interleukin-1 in the pathogenesis and treatment of inflammatory diseases SIGNOR-171873 0.7 GLS protein O94925 UNIPROT Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 28053289 f Glutaminase is the rate-limiting enzyme in glutaminolysis and it is encoded by two different genes, GLS and GLS2. SIGNOR-259999 0.7 A5/b1 integrin complex SIGNOR-C163 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity 15721307 f lperfetto Previous reports indicated that the prosurvival signal mediated through α5β1-fibronectin interactions was due to increased Bcl-2 levels SIGNOR-253310 0.2 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207102 0.8 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. SIGNOR-167152 0.843 APOC3 protein P02656 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 17315402 f Regulation miannu Apolipoprotein CIII inhibits the lipoprotein lipase. SIGNOR-251850 0.647 AGPAT3 protein Q9NRZ7 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 12401205 t gcesareni Pa can be generated by the acylation of lyso-pa by lyso-pa acyl transferases SIGNOR-94864 0.8 MPO-ANCA complex SIGNOR-C474 SIGNOR ROS stimulus SIGNOR-ST2 SIGNOR up-regulates -1 2161532 f lperfetto ANCA-induced release of ROS measured by chemiluminescence. SIGNOR-270590 0.7 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser359 SPSTPVGsPQGLAGT 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161531 0.2 F2 protein P00734 UNIPROT F2RL2 protein O00254 UNIPROT up-regulates binding 9606 11356985 t gcesareni as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells SIGNOR-108225 0.653 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor. SIGNOR-21193 0.934 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity 10090 BTO:0004732 26208884 f The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12. SIGNOR-256080 0.2 regorafenib chemical CHEBI:68647 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206415 0.8 GSK690693 chemical CHEBI:90677 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193000 0.8 STC2 protein O76061 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 10090 BTO:0000298 29207625 f lperfetto STC2 activates STAT3 signaling pathway in the hypothalamus and GT1-7 cells SIGNOR-260406 0.2 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190720 0.8 seliciclib chemical CHEBI:45307 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206565 0.8 SKP1 protein P63208 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 t gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. SIGNOR-64514 0.895 ARSA protein P15289 UNIPROT HBA1 protein P69905 UNIPROT up-regulates activity acetylation 9606 237937 t Regulation miannu ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction. SIGNOR-251773 0.2 6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline chemical CHEBI:91417 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193522 0.8 orantinib chemical CHEBI:91088 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207441 0.8 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206163 0.8 GDF2 protein Q9UK05 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 f gcesareni Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs SIGNOR-183535 0.255 MK-2461 chemical CID:44137946 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194384 0.8 LRIG1 protein Q96JA1 UNIPROT LRIG3 protein Q6UXM1 UNIPROT down-regulates 9606 23723069 f miannu Lrig1 destabilizes lrig3, limiting lrig3's positive effects on receptors and identifying lrig3 as a new target of lrig1. SIGNOR-202177 0.433 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e. SIGNOR-166646 0.779 MET protein P08581 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 8662889 t gcesareni To efficiently promote transformation met requires direct binding with grb2. SIGNOR-42358 0.269 Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate chemical CID:46907787 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 20871596 t Simone Vumbaca JQ1 displaces BRD4 from nuclear chromatin in cells SIGNOR-261123 0.8 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 BTO:0000567 12637538 t Abl Phosphorylates and Activates PKD through Tyr463 Phosphorylation SIGNOR-251430 0.339 COL2A1 protein P02458 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates binding 9606 9685391 t gcesareni We have isolated a novel collagen type ii binding integrin, a10b1, SIGNOR-59349 0.49 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 12408982 t gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. SIGNOR-95242 0.417 SGI-1776 chemical CID:24795070 PUBCHEM PIM3 protein Q86V86 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206896 0.8 BUB1 protein O43683 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 f gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) SIGNOR-168192 0.7 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO1 protein P49895 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001379 27347897 t scontino The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU). SIGNOR-267280 0.8 CUL4A protein Q13619 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 t lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes SIGNOR-154502 0.9 CCT129202 chemical CID:16202152 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190880 0.8 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22972936 t milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-199010 0.565 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207248 0.8 CADM2 protein Q8N3J6 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 BTO:0000962 17967169 f Gianni The adhesion molecule Necl-3/SynCAM-2 localizes to myelinated axons, binds to oligodendrocytes and promotes cell adhesion. SIGNOR-268856 0.7 progesterone smallmolecule CHEBI:17026 ChEBI COMT protein P21964 UNIPROT down-regulates 17138778 f Regulation of expression miannu Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen. SIGNOR-251960 0.8 CHIR-124 chemical CID:11502647 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190973 0.8 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205939 0.8 FOXO3 protein O43524 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 f gcesareni Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. SIGNOR-241949 0.7 CDK18 protein Q07002 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation -1 28361970 t lperfetto Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  SIGNOR-264558 0.287 R406 chemical CID:11984591 PUBCHEM SYK protein P43405 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206340 0.8 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194913 0.8 GSK256066 chemical CID:9827968 PUBCHEM PDE4B protein Q07343 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192982 0.8 LHX2 protein P50458 UNIPROT CGA protein P01215 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 7513049 t Luana In Cos cells, LH-2 activated the a-subunit promoter approximately twofold SIGNOR-266055 0.266 LTBR protein P36941 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 17633025 f lperfetto The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. SIGNOR-156902 0.7 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 21658950 t miannu Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis SIGNOR-262656 0.2 NUMA1 protein Q14980 UNIPROT TUBB protein P07437 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116900 0.404 SFPQ protein P23246 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 23308148 t miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. SIGNOR-223970 0.446 CSNK2A2 protein P19784 UNIPROT HNRNPC protein P07910 UNIPROT unknown phosphorylation Ser260 SEGGADDsAEEGDLL -1 12564933 t llicata Protein kinase CK2 phosphorylates hnRNP-C1/C2 at S247 SIGNOR-251007 0.326 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207606 0.8 A6/b1 integrin complex SIGNOR-C164 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269013 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-256474 0.7 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190224 0.8 OGT protein O15294 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity glycosylation Ser430 VDRLRRMsLIEEEGS 9606 BTO:0002181 34939084 t Luana O-GlcNAcylation at Ser-430 promotes PYGL activity SIGNOR-267988 0.2 PPP1R2 protein P41236 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates binding 9606 18250156 t gcesareni Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. SIGNOR-160651 0.785 NCOR2 protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t Ncor2 is a Skip corepressor gcesareni Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt. SIGNOR-74227 0.591 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193531 0.8 HDAC1 protein Q13547 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 17183360 t gcesareni Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1. SIGNOR-151425 0.571 AKT1 protein P31749 UNIPROT PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 f gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. SIGNOR-252490 0.251 MAPK8 protein P45983 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t gcesareni Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. SIGNOR-173417 0.308 Arry-380 chemical CID:42598643 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189882 0.8 PTPRB protein P23467 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21454675 t fstefani Expression of rptp-beta inhibits both mek1/2 and erk1/2 phosphorylation. SIGNOR-173000 0.382 imatinib methanesulfonate chemical CHEBI:31690 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193393 0.8 pelitinib chemical CHEBI:38927 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205755 0.8 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Azd7762 is equally potent against chk2 in vitro. SIGNOR-163119 0.8 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT unknown phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto Dapk phosphorylates camkks511 was identified as the phosphorylation site SIGNOR-126245 0.283 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 t milica This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain. SIGNOR-163545 0.71 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr465 GEEELSNyICMGGKG 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157738 0.868 EIF4A2 protein Q14240 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 BTO:0000671 11408474 t miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. SIGNOR-108512 0.817 CEBPA protein P49715 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity binding 9606 BTO:0004116 7862113 t irozzo Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study. SIGNOR-255701 0.317 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190302 0.8 NEK2 protein P51955 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation 9606 15161910 t esanto Nek2 directly phosphorylated nek11 in the c-terminal non-catalytic region and elevated nek11 kinase activity. SIGNOR-124944 0.393 AMPK complex SIGNOR-C15 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 12065600 t lperfetto Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro. SIGNOR-216639 0.393 WNT1 protein P04628 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 11448771 t gcesareni Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd) SIGNOR-109250 0.725 CDA protein P32320 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 24183806 t miannu Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively.  SIGNOR-280618 CDA protein P32320 UNIPROT uridine smallmolecule CHEBI:16704 ChEBI up-regulates quantity chemical modification 9606 24183806 t miannu Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively.  SIGNOR-280619 DGUOK protein Q16854 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280569 0.8 DGUOK protein Q16854 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280570 0.8 DGUOK protein Q16854 UNIPROT 2'-deoxyadenosine smallmolecule CHEBI:17256 ChEBI down-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280571 0.8 DGUOK protein Q16854 UNIPROT 2'-deoxyadenosine 5'-monophosphate(2-) smallmolecule CHEBI:58245 ChEBI up-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280572 0.8 DGUOK protein Q16854 UNIPROT 2'-deoxyguanosine smallmolecule CHEBI:17172 ChEBI down-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280573 0.8 DGUOK protein Q16854 UNIPROT 2'-deoxyguanosine 5'-monophosphate(2-) smallmolecule CHEBI:57673 ChEBI up-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280574 0.8 DGUOK protein Q16854 UNIPROT 2'-deoxyinosine smallmolecule CHEBI:28997 ChEBI down-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280575 0.8 CDA protein P32320 UNIPROT cytidine smallmolecule CHEBI:17562 ChEBI down-regulates quantity chemical modification 9606 24183806 t miannu Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively.  SIGNOR-280620 CDA protein P32320 UNIPROT 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI down-regulates quantity chemical modification 9606 24183806 t miannu Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively.  SIGNOR-280621 CDA protein P32320 UNIPROT 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI up-regulates quantity chemical modification 9606 24183806 t miannu Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively.  SIGNOR-280622 uridine smallmolecule CHEBI:16704 ChEBI cytidine smallmolecule CHEBI:17562 ChEBI up-regulates quantity precursor of 9606 24183806 t miannu Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively.  SIGNOR-280623 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI up-regulates quantity precursor of 9606 24183806 t miannu Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively.  SIGNOR-280624 GSK3B protein P49841 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 33081032 t miannu GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371. SIGNOR-263513 0.359 TK1 protein P04183 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 17407781 t miannu The two dTTP biosynthetic routes are the de novo and the salvage pathways. Human thymidine kinase 1 (hTK1) catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. SIGNOR-280519 0.8 CBLB protein Q13191 UNIPROT TYRO3 protein Q06418 UNIPROT up-regulates activity ubiquitination 9606 31531847 t miannu Consistent with these data, we also found that Tyro3 is ubiquitinated by Cbl-b.|These data suggest that not only was Tyro3 a ubiquitination target of Cbl-b, but also that Cbl-b was a phosphorylation target of Tyro3. SIGNOR-278807 0.35 GMPR protein P36959 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI up-regulates quantity chemical modification 9606 33369428 t miannu The human GMPR enzyme maintains the intracellular balance between the adenine and guanine nucleotide pools. The chemical reaction of this enzyme proceeds by deamination and hydride transfer steps. In deamination, the thiol group of Cys186 reacts on C2 of 5GP to form an intermediate E-XMP. In the second step, nicotinamide moves adjacent to C2 of E-XMP to allow hydride ion transfer, resulting in the production of inosine-5′-monophosphate (IMP) (Figure S4).  SIGNOR-280514 0.8 guanosine 5'-monophosphate(2-) smallmolecule CHEBI:58115 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 33369428 t miannu The human GMPR enzyme maintains the intracellular balance between the adenine and guanine nucleotide pools. The chemical reaction of this enzyme proceeds by deamination and hydride transfer steps. In deamination, the thiol group of Cys186 reacts on C2 of 5GP to form an intermediate E-XMP. In the second step, nicotinamide moves adjacent to C2 of E-XMP to allow hydride ion transfer, resulting in the production of inosine-5′-monophosphate (IMP) (Figure S4).  SIGNOR-280515 0.8 TK1 protein P04183 UNIPROT thymidine smallmolecule ChEBI:17748 ChEBI down-regulates quantity chemical modification 9606 17407781 t miannu The two dTTP biosynthetic routes are the de novo and the salvage pathways. Human thymidine kinase 1 (hTK1) catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. SIGNOR-280516 0.8 TK1 protein P04183 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 17407781 t miannu The two dTTP biosynthetic routes are the de novo and the salvage pathways. Human thymidine kinase 1 (hTK1) catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. SIGNOR-280517 0.8 9-cis-retinoic acid chemical CHEBI:50648 ChEBI FOXP3 protein Q9BZS1 UNIPROT up-regulates activity transcriptional regulation 9606 BTO:0005453 18684916 f Tiberia RA enhances TGF-β signaling by increasing the expression and phosphorylation of Smad3 and this translates into increased Foxp3 expression. SIGNOR-280617 0.8 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide chemical CHEBI:125569 ChEBI PPARG protein P37231 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001950 27489280 t lperfetto We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A) SIGNOR-262015 0.8 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 0.307 PRKACA protein P17612 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 18768928 t llicata The results indicate that phosphorylation of gdi_ at ser174 by pka suppresses rhoa activity, providing a potential protective signaling mechanism for inflammatory injury. SIGNOR-180576 0.387 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 29479476 t miannu The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. Axon guidance assays confirm that this DCC/FAK complex is physiologically essential for netrin-1-induced chemoattraction. SIGNOR-268370 0.72 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LCK protein P06239 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 8618896 t inferred from 70% family members lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. SIGNOR-270074 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation Ser584 EPGQRQPsEQELLFR -1 30661366 t miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. SIGNOR-277423 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251598 0.704 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21041712 t gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. SIGNOR-169194 0.8 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys17 GLGKGGAkRHRKVLR 9606 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. SIGNOR-267166 0.2 UBE4B protein O95155 UNIPROT MAPT protein P10636 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 34078905 t miannu Ubiquitination and degradation of Tau by UBE4B and STUB1 in mammalian neuroblastoma cells. SIGNOR-278682 0.2 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270896 0.546 KDM3B protein Q7LBC6 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. SIGNOR-266634 0.2 ITGB1BP1 protein O14713 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257657 0.279 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120196 0.316 CDK1 protein P06493 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 t lperfetto Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. SIGNOR-264648 0.576 CDKL5 protein O76039 UNIPROT SOX9 protein P48436 UNIPROT down-regulates activity phosphorylation Ser199 ATEQTHIsPNAIFKA 9606 32317630 t miannu Based on these studies, we hypothesized that Cdkl5 dependent phosphorylation at Ser 199 suppresses Sox9 function during AKI.|We also found that Cdkl5 phosphorylates Sox9 at Ser 199 residue during kidney injury in vivo. SIGNOR-279457 0.2 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.819 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates activity binding 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258411 0.668 RPS2 protein P15880 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262431 0.907 AKT proteinfamily SIGNOR-PF24 SIGNOR SIK1 protein P57059 UNIPROT down-regulates activity phosphorylation Ser435 VFRPRPVsPSSLLDT 9606 BTO:0000007 36806887 t miannu  Mass spectrometry-based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions.  SIGNOR-277835 0.2 CDKL5 protein O76039 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT unknown phosphorylation Ser631 PLLIRMNsKDNVQET 9606 22922712 t llicata Cdkl5 binds and phosphorylates the cell adhesion molecule ngl-1. This phosphorylation event ensures a stable association between ngl-1 and psd95. SIGNOR-192035 0.428 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 0.26 TRIO protein O75962 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity binding 10116 BTO:0004102 23230270 t miannu TrioY2622 is required for both netrin-1-induced activation of Rac1 and enhanced association with DCC. Phosphorylation of Trio at Tyr2622 participates in maintaining the level of surface DCC at the growth cone plasma membrane leading to axon outgrowth. Therefore, we propose that TrioY2622 is essential for the proper assembly and stability of the DCC/Trio signaling complex at the cell surface of growth cones in order to mediate netrin-1-induced cortical axon outgrowth. SIGNOR-273856 0.606 TNK2 protein Q07912 UNIPROT WWP2 protein O00308 UNIPROT up-regulates activity phosphorylation 9606 36773333 t miannu ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity.|Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1. SIGNOR-279302 0.342 PJA2 protein O43164 UNIPROT PRKAR2B protein P31323 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 t miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits SIGNOR-271858 0.2 PRKACA protein P17612 UNIPROT SYN2 protein Q92777 UNIPROT down-regulates activity phosphorylation Ser10 NFLRRRLsDSSFIAN -1 10571231 t miannu Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I SIGNOR-250059 0.326 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys64 RAGCCLGkAVRGAKG 9606 17098745 t gcesareni Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells. SIGNOR-150595 0.441 FGF2 protein P09038 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates 9606 20974802 f 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-168995 0.602 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264155 0.768 PPM1B protein O75688 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity dephosphorylation -1 22750291 t lperfetto PPM1B dephosphorylates TBK1 in vivo and in vitro.|These results demonstrate that PPM1B inhibits TBK1 mediated antiviral signaling by directly dephosphorylating TBK1 at Ser172. SIGNOR-276985 0.352 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr72 IKALRTDyNASVSVP 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88919 0.603 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Thr5 tPDEKLRL 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275597 0.249 ACSL1 protein P33121 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity chemical modification 9606 21242590 t miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). SIGNOR-267877 0.8 NLK protein Q9UBE8 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 26588989 t done miannu NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.  SIGNOR-273908 0.327 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 0.723 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser561 MANDSDDsISAATNK -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265894 0.2 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 0.502 Endoplasmic reticulum membrane complex- EMC9 variant complex SIGNOR-C566 SIGNOR Protein_insertion_into_membrane phenotype SIGNOR-PH236 SIGNOR up-regulates 9606 32439656 f miannu The nine-subunit ER membrane protein complex (EMC) is a conserved co- and post-translational insertase at the endoplasmic reticulum. We determined the structure of the human EMC in a lipid nanodisc to an overall resolution of 3.4 Å by cryo-electron microscopy, permitting building of a nearly complete atomic model.  SIGNOR-280646 Endoplasmic reticulum membrane complex, EMC8 variant complex SIGNOR-C567 SIGNOR Protein_insertion_into_membrane phenotype SIGNOR-PH236 SIGNOR up-regulates 9606 32439656 f miannu A defining step in the biogenesis of a membrane protein is the insertion of its hydrophobic transmembrane helices into the lipid bilayer. The nine-subunit endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved co- and posttranslational insertase at the ER. SIGNOR-280656 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 14968113 t lperfetto Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation SIGNOR-122094 0.731 HDAC1 protein Q13547 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-134059 0.697 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000876 14701740 t inferred from 70% family members lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. SIGNOR-270066 0.2 IFNL2 protein Q8IZJ0 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96206 0.71 STK38 protein Q15208 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser288 KGHTRNKsTSSAMSG 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263036 0.366 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr519 PPREEDCySETEAED 26319181 t lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. SIGNOR-275918 0.506 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266501 0.8 YARS1 protein P54577 UNIPROT tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI down-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270517 0.8 DNMT3B protein Q9UBC3 UNIPROT IL32 protein P24001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 20889550 f lperfetto A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. SIGNOR-254127 0.2 DLG2 protein Q15700 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270909 0.503 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 0.2 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258799 0.8 terbutaline chemical CHEBI:9449 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257870 0.8 CSNK2A2 protein P19784 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-275741 0.307 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 0.671 EPHA3 protein P29320 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr552 DHVLPIDyYFPPQKT 9606 20570899 t miannu These data suggest that Etk may be able to phosphorylate AR at Y534 and Y551/552, and the interaction between the Etk SH2 domain and phosphorylated ARY551/552 may promote their association.|This is supported by our observations that the association between Etk and AR is increased after castration and Etk induces tyrosine phosphorylation of AR, leading an increase in AR stability and transcriptional activity under androgen depleted conditions. SIGNOR-279371 0.273 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 0.2 GSK3B protein P49841 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr1938 HREKKEStPSTASLP 10116 BTO:0000938 29642012 t lperfetto In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity. SIGNOR-275763 0.2 PRKCQ protein Q04759 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 26431586 f lperfetto It is known that the teta isoform of the PKC family promotes the fusion of myoblasts and regulates the expression of caveolin-3 and beta1D integrin [15]. Of note, it has also been demonstrated that PKCepsilon expression increases during insulin-induced myogenic differentiation of the C2C12 cells. SIGNOR-241525 0.2 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190708 0.8 NUTF2 protein P61970 UNIPROT NUP62 protein P37198 UNIPROT up-regulates activity binding 9606 BTO:0000567 7744965 t Simone Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol. SIGNOR-261255 0.845 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 8548810 t lperfetto The c-iaps associate with traf1 and traf3 SIGNOR-39527 0.873 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Ala) smallmolecule CHEBI:29170 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280701 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280702 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Asn) smallmolecule CHEBI:29172 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280703 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Asp) smallmolecule CHEBI:29186 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280704 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Cys) smallmolecule CHEBI:29167 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280705 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280706 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280707 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Gly) smallmolecule CHEBI:29176 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280708 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(His) smallmolecule CHEBI:29178 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280709 Met-tRNA(Met) chemical CHEBI:16635 ChEBI Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269117 0.8 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Ile) smallmolecule CHEBI:29174 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280710 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280711 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280712 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280713 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280714 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280715 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Ser) smallmolecule CHEBI:29179 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280716 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Thr) smallmolecule CHEBI:29180 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280717 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Trp) smallmolecule CHEBI:29181 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280718 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280719 Nucleolar ribonuclease P complex complex SIGNOR-C571 SIGNOR tRNA(Val) smallmolecule CHEBI:29183 ChEBI up-regulates quantity chemical modification 9606 30454648 t miannu Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. SIGNOR-280720 GTF2I protein P78347 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity binding 9606 21282467 t lperfetto TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription SIGNOR-268538 0.489 SPOP protein O43791 UNIPROT GMNN protein O75496 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 34599168 t miannu SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. SIGNOR-268926 0.2 RASGEF1B protein Q0VAM2 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183832 0.376 ritonavir chemical CHEBI:45409 ChEBI CYP2B6 protein P20813 UNIPROT up-regulates activity chemical activation 9606 18285471 t Luana These results show that ritonavir induces human CYP2B6 activity.  SIGNOR-257770 0.8 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR 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-204822 0.2 CatSpermasome complex complex SIGNOR-C574 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 25457194 t miannu Cation channel of sperm (CatSper) is a sperm-specific, weakly voltage-dependent, Ca2+ selective, pH-sensitive ion channel that controls the entry of positively charged calcium ions into sperm cells, which is essential for sperm hyperactivation and male fertility SIGNOR-280745 PP121 chemical CHEBI:50915 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206301 0.8 TLR9 protein Q9NR96 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266742 0.678 GNAQ protein P50148 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 9235901 t gcesareni Galfaq/11 subunits also activate p21ras SIGNOR-50104 0.641 Nexin-dynein regulatory complex complex SIGNOR-C575 SIGNOR Microtubule-based_movement phenotype SIGNOR-PH170 SIGNOR up-regulates 9606 37258679 f miannu The nexin–dynein regulatory complex (N-DRC) is a conserved structural protein complex present in the axonemes of cilia/flagella, from algae to humans. Moreover, it is composed of at least 11 components (DRC1–11) and is critical for ciliary/flagellar motility, functioning by linking the outer adjacent duplex microtubules SIGNOR-280757 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 0.289 Ribonuclease MRP complex complex SIGNOR-C570 SIGNOR ribosomal RNA smallmolecule CHEBI:18111 ChEBI up-regulates quantity chemical modification 9606 40413743 t miannu Human RNase MRP is a ribonucleoprotein (RNP) enzyme that processes precursor rRNA (pre-rRNA) at ITS1 site 2 and may have additional activities.Using a genome-wide forward genetic screening that leveraged the requirement of RNase MRP and RNase P for reporter translation, we identified two poorly characterized yet highly enriched human genes, c18orf21 and c3orf17, which we named ribonuclease MRP subunit P24 (RMP24) and RMP64, respectively. We demonstrate that these two genes are specifically required for the activity of human RNase MRP but not RNase P. The protein products of RMP24 and RMP64 associate extensively and exclusively with the only known human RNase MRP-specific component, MRP RNA, but not with the RNase P-specific H1 RNA. Our findings establish Rmp24 and Rmp64 as human protein components unique to RNase MRP. SIGNOR-280690 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 0.435 ADX-47273 chemical CID:11383075 PUBCHEM MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates chemical activation 9606 Other t Selleck|inferred from family member gcesareni SIGNOR-270276 0.8 Signal peptidase complex, SEC11A variant complex SIGNOR-C582 SIGNOR Protein_maturation phenotype SIGNOR-PH237 SIGNOR up-regulates 9606 34388369 f miannu Nascent SPs emerge from the ribosome and target the ribosome-nascent-chain complex to the ER membrane, where it is inserted into the protein-conducting channel Sec61 (Gemmer and Förster, 2020). For many proteins (approximated to exceed 3,000 different physiological protein substrates in humans (Uhlén et al., 2015)), the signal peptidase complex (SPC) cleaves off the SPs from their non-functional pre-forms. SIGNOR-280778 Signal peptidase complex, SEC11C variant complex SIGNOR-C581 SIGNOR Protein_maturation phenotype SIGNOR-PH237 SIGNOR up-regulates 9606 34388369 f miannu Nascent SPs emerge from the ribosome and target the ribosome-nascent-chain complex to the ER membrane, where it is inserted into the protein-conducting channel Sec61 (Gemmer and Förster, 2020). For many proteins (approximated to exceed 3,000 different physiological protein substrates in humans (Uhlén et al., 2015)), the signal peptidase complex (SPC) cleaves off the SPs from their non-functional pre-forms. SIGNOR-280779 INSR protein P06213 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation Tyr398 ARVKEEGyELPYNPA 10029 BTO:0000246 11551902 t Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway. SIGNOR-251308 0.562 SB 431542 chemical CHEBI:91108 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206706 0.8 TNFSF13 protein O75888 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 10956646 t gcesareni Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys. SIGNOR-81308 0.71 beta-alanine smallmolecule CHEBI:16958 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-258581 0.8 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 0.718 DOT1L protein Q8TEK3 UNIPROT HECTD4 protein Q9Y4D8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly. SIGNOR-267150 0.2 CHD2 protein O14647 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 29962935 t miannu CHD2 also showed an interaction with MyoD, a master regulator of skeletal muscle differentiation, and together MyoD and CHD2 bind to myogenic gene promoters. SIGNOR-264525 0.2 CDK1 protein P06493 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates activity phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 BTO:0000567 21642957 t done miannu We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1. SIGNOR-273889 0.482 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 0.953 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates activity dephosphorylation 9606 12857726 t Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation SIGNOR-248403 0.504 GPT2 protein Q8TD30 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 11863375 t 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-266925 0.8 SEC61 complex complex SIGNOR-C368 SIGNOR Protein_maturation phenotype SIGNOR-PH237 SIGNOR up-regulates 9606 35940906 f miannu The endoplasmic reticulum (ER) is a major site for protein synthesis, folding, and maturation in eukaryotic cells, responsible for production of secretory proteins and most integral membrane proteins. The universally conserved protein-conducting channel Sec61 complex mediates core steps in these processes by translocating hydrophilic polypeptide segments of client proteins across the ER membrane and integrating hydrophobic transmembrane segments into the membrane. The Sec61 complex associates with several other molecular machines and enzymes to enable substrate engagement with the channel and coordination of protein translocation with translation, protein folding, and/or post-translational modifications. SIGNOR-280795 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates activity phosphorylation Ser495 KTMIRKRsFGNPFEG 9534 BTO:0000298 32913128 t miannu  Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues.  SIGNOR-277238 0.2 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 0.283 Nax cation channel complex SCN2B-SCN3B variant complex SIGNOR-C583 SIGNOR sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 26042603 t miannu Nax is a sodium-concentration ([Na+])-sensitive Na channel with a gating threshold of ~150 mM for extracellular [Na+] ([Na+]o) in vitro. We previously reported that Nax was preferentially expressed in the glial cells of sensory circumventricular organs including the subfornical organ, and was involved in [Na+] sensing for the control of salt-intake behavior.  SIGNOR-280816 Nax cation channel complex, SCN3B-SCN4B variant complex SIGNOR-C584 SIGNOR sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 26042603 t miannu Nax is a sodium-concentration ([Na+])-sensitive Na channel with a gating threshold of ~150 mM for extracellular [Na+] ([Na+]o) in vitro. We previously reported that Nax was preferentially expressed in the glial cells of sensory circumventricular organs including the subfornical organ, and was involved in [Na+] sensing for the control of salt-intake behavior.  SIGNOR-280817 Nax cation channel complex, SCN1B-SCN4B variant complex SIGNOR-C585 SIGNOR sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 26042603 t miannu Nax is a sodium-concentration ([Na+])-sensitive Na channel with a gating threshold of ~150 mM for extracellular [Na+] ([Na+]o) in vitro. We previously reported that Nax was preferentially expressed in the glial cells of sensory circumventricular organs including the subfornical organ, and was involved in [Na+] sensing for the control of salt-intake behavior.  SIGNOR-280818 Nax cation channel complex, SCN1B-SCN2B variant complex SIGNOR-C586 SIGNOR sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 26042603 t miannu Nax is a sodium-concentration ([Na+])-sensitive Na channel with a gating threshold of ~150 mM for extracellular [Na+] ([Na+]o) in vitro. We previously reported that Nax was preferentially expressed in the glial cells of sensory circumventricular organs including the subfornical organ, and was involved in [Na+] sensing for the control of salt-intake behavior.  SIGNOR-280819 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 0.65 U3 snoRNP complex SIGNOR-C589 SIGNOR ribosomal RNA smallmolecule CHEBI:18111 ChEBI up-regulates quantity binding 9606 29414516 t miannu The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. Eukaryotic ribosome biogenesis is initiated by the seven-subunit UtpA complex (Utp4, Utp5, Utp8, Utp9, Utp10, Utp15 & Utp17). UtpA binding and the presence of additional parts of the 5′ ETS appear to be required for the subsequent recruitment of the six-subunit UtpB complex (Utp1/Pwp2, Utp6, Utp12, Utp13, Utp18 & Utp21) and the U3 snoRNP (U3 snoRNA, Nop1/fibrillarin, Snu13, Nop56 & Nop58) SIGNOR-280833 UTP-A complex complex SIGNOR-C587 SIGNOR ribosomal RNA smallmolecule CHEBI:18111 ChEBI up-regulates quantity binding 9606 29414516 t miannu The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. Eukaryotic ribosome biogenesis is initiated by the seven-subunit UtpA complex (Utp4, Utp5, Utp8, Utp9, Utp10, Utp15 & Utp17). UtpA binding and the presence of additional parts of the 5′ ETS appear to be required for the subsequent recruitment of the six-subunit UtpB complex (Utp1/Pwp2, Utp6, Utp12, Utp13, Utp18 & Utp21) and the U3 snoRNP (U3 snoRNA, Nop1/fibrillarin, Snu13, Nop56 & Nop58) SIGNOR-280834 UTP-B complex complex SIGNOR-C588 SIGNOR ribosomal RNA smallmolecule CHEBI:18111 ChEBI up-regulates quantity binding 9606 29414516 t miannu The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. Eukaryotic ribosome biogenesis is initiated by the seven-subunit UtpA complex (Utp4, Utp5, Utp8, Utp9, Utp10, Utp15 & Utp17). UtpA binding and the presence of additional parts of the 5′ ETS appear to be required for the subsequent recruitment of the six-subunit UtpB complex (Utp1/Pwp2, Utp6, Utp12, Utp13, Utp18 & Utp21) and the U3 snoRNP (U3 snoRNA, Nop1/fibrillarin, Snu13, Nop56 & Nop58) SIGNOR-280835 POU5F1 protein Q01860 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253163 0.455 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 0.2 TM9SF4 protein Q92544 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity binding 9606 BTO:0000007 29125601 t miannu TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death. SIGNOR-266703 0.2 NDUFB5 protein O43674 UNIPROT NADH-ubiquinone oxidoreductase-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 0.83 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 0.575 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 0.777 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 0.395 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 0.673 IRX1 protein P78414 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261660 0.2 DRD3 protein P35462 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264994 0.452 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 0.464 IFNG protein P01579 UNIPROT IL6 protein P05231 UNIPROT up-regulates activity transcriptional regulation 9606 BTO:0000375 9198002 f Tiberia IFN-gamma (10-50 ng/ml) induced IL-6 and IL-8 production dose dependently. SIGNOR-280842 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 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15048722 f We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription SIGNOR-254497 0.424 HADH protein Q16836 UNIPROT (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI down-regulates quantity chemical modification 9606 16176262 t miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. SIGNOR-280423 0.8 CDK2 protein P24941 UNIPROT SOX2 protein P48431 UNIPROT up-regulates activity phosphorylation Ser251 VKSEASSsPPVVTSS -1 26139602 t miannu Cdk2 physically interacts with Sox2 and phosphorylates Sox2 at Ser 39 and Ser 253 in vitro.|Cyclin-dependent kinase-mediated Sox2 phosphorylation enhances the ability of Sox2 to establish the pluripotent state SIGNOR-279449 0.394 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT up-regulates phosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000975 1849884 t lperfetto Role of threonine-286 as autophosphorylation site for appearance of ca2(+)-independent activity of calmodulin-dependent protein kinase ii alpha subunit SIGNOR-21797 0.2 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser453 TNTHTQSsSSSSDGG 9606 BTO:0000007 22216226 t miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  SIGNOR-276366 0.929 CHMP1B protein Q7LBR1 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-265524 0.713 LTK protein P29376 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells. SIGNOR-49625 0.424 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 0.253 SDF2L1 protein Q9HCN8 UNIPROT LRP4 protein O75096 UNIPROT up-regulates activity binding 9606 BTO:0000007 24140340 t llicata Here, we show that the chaperon Mesdc2 binds to the intracellular form of Lrp4 and promotes its glycosylation and cell-surface expression. These results suggest that Mesdc2 plays an essential role in NMJ formation by promoting Lrp4 maturation. SIGNOR-237942 0.2 PZP protein P20742 UNIPROT MMP2 protein P08253 UNIPROT down-regulates activity binding -1 9344465 t lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261804 0.329 ATP13A1 protein Q9HD20 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004093 29650961 f doi.org/10.1101/185272 francesca Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions SIGNOR-261217 0.7 CTBP1 protein Q13363 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21681822 t irozzo Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. SIGNOR-259196 0.603 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-249604 0.391 EEF1A1 protein P68104 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0000608 37973952 t Marta Tosoni Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription SIGNOR-278105 0.2 arachidonic acid smallmolecule CHEBI:15843 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates 9606 15878913 f miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255393 0.8 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 0.568 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates activity dephosphorylation Tyr291 AETSKLIyDFIEDQG 10090 14707117 t Mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities|WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST SIGNOR-248660 0.444 CoQ biosynthetic complex complex SIGNOR-C591 SIGNOR coenzyme Q10 smallmolecule CHEBI:46245 ChEBI up-regulates quantity chemical modification 9606 38425362 t miannu Metabolons are protein assemblies that perform a series of reactions in a metabolic pathway. However, the general importance and aptitude of metabolons for enzyme catalysis remain poorly understood. In animals, biosynthesis of coenzyme Q is currently attributed to ten different proteins, with COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9 forming the iconic COQ metabolon. SIGNOR-280849 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 0.435 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 0.389 TIMP2 protein P16035 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10116 BTO:0001860 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-265254 0.2 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 0.371 ZBTB46 protein Q86UZ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 30962287 t miannu We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling. SIGNOR-277987 0.2 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 0.39 PRKCA protein P17252 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-66666 0.441 WWP2 protein O00308 UNIPROT POLR2A protein P24928 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0001938 31048545 t lperfetto WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks|In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. SIGNOR-268851 0.387 CAPRIN2 protein Q6IMN6 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0000007 35051932 t lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|Altogether, the data indicate that CAPRIN2 binds Oxt mRNA |Therefore, we propose that CAPRIN2 facilitates post-transcriptional modifications that increase Oxt transcript stability. SIGNOR-268556 0.2 degarelix chemical CHEBI:135961 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-259160 0.8 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. SIGNOR-151015 0.2 CHMP2A protein O43633 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-265532 0.77 ALDOB protein P05062 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266480 0.8 AP-4 Adaptor complex complex SIGNOR-C590 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 9606 23167973 f miannu  The adaptor proteins (APs) are a family of five heterotetrameric complexes with important functions in vesicle trafficking. The predominant steady-state localization of a sorting adaptor usually indicates the donor compartment of the mediated transport step, suggesting that AP-4 is involved in sorting at the TGN. The simplest model that emerges from these findings suggests that AP-4 mediates anterograde trafficking between the TGN and an endosomal compartment (Figure 1). SIGNOR-280855 POLR2L protein P62875 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-266171 0.861 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates phosphorylation 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-255032 0.722 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 0.699 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 0.2 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 t lperfetto Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. SIGNOR-275584 0.2 VCP protein P55072 UNIPROT DDX58 protein O95786 UNIPROT down-regulates quantity by destabilization ubiquitination Lys181 ALEKERNkFSELWIV 9606 26471729 t lperfetto Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. SIGNOR-261000 0.2 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 9162089 t gcesareni However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2. SIGNOR-48561 0.522 D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity relocalization 9606 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-263259 0.677 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 0.2 PIM1 protein P11309 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation 9606 16684349 t miannu Furthermore, catalytically active Pim-1 kinase was able to phosphorylate Runx1 and Runx3 proteins and enhance the transactivation activity of Runx1 in a dose-dependent fashion.|Pim-1 potentiates transcriptional activity of the RUNX1 transcription factor. SIGNOR-278976 0.269 SRC protein P12931 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Tyr54 YLKERRVyVTLTCAF 9606 17456551 t lperfetto Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors. SIGNOR-154564 0.684 SF3A1 protein Q15459 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 t miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263948 0.973 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 ASAAGGLsPVTNLTV 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277343 0.628 MCU_MICU1_variant complex SIGNOR-C500 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-270868 0.8 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 0.606 HDAC2 protein Q92769 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28793257 f Among histone-modifying enzymes, HDAC2 is a crit- ical negative regulator of structural and functional plasticity in the mammalian nervous system (Guan et al., 2009; Hanson et al., 2013). HDAC2 localizes to the promoters of numerous synap- tic-plasticity-associated genes, where it deacetylates histone substrates (Gra ̈ ff et al., 2012; Guan et al., 2009). Consistently, loss of HDAC2 or HDAC inhibitor treatments promotes synaptic gene expression, long-term synaptic plasticity, and memory pro- cesses, while HDAC2 overexpression has opposing effects SIGNOR-268624 0.7 HACD2 protein Q6Y1H2 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-267761 0.2 TRAF6 protein Q9Y4K3 UNIPROT IL1R1 protein P14778 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19232518 t miannu We found that of all TRAFs and E3 ligases examined, TRAF6 preferentially ubiquitinated IL-1R1. SIGNOR-278576 0.9 panobinostat chemical CHEBI:85990 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-257751 0.8 ATM protein Q13315 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity phosphorylation Ser141 DYNETDWsQEFISEV 9606 BTO:0000007 26344566 t Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.  SIGNOR-262792 0.497 MMP14 protein P50281 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. SIGNOR-263610 0.331 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266250 0.8 TNF protein P01375 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 11287630 f gcesareni Irs-1 tyrosine phosphorylation by tnf was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mtor), a downstream target of akt. these results suggest that tnf impairs insulin signaling through irs-1 SIGNOR-106599 0.395 F2RL3 protein Q96RI0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22318735 t gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). SIGNOR-196012 0.485 DLG4 protein P78352 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270889 0.472 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t gcesareni Serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation. SIGNOR-86141 0.5 MAVS protein Q7Z434 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22588174 f Giorgia ECSIT enhances IPS-1-mediated IFN-Beta promoter activation SIGNOR-260372 0.487 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 9271428 t gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. SIGNOR-50594 0.2 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser171 VTHDLRVsLEEIYSG 9606 24309468 t lperfetto Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1. SIGNOR-203464 0.463 FOXH1 protein O75593 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 BTO:0001538 9858566 t lperfetto FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1. SIGNOR-108333 0.778 MMP20 protein O60882 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272365 0.7 SRC protein P12931 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 t miannu Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. SIGNOR-277520 0.42 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr514 PATPKYAtPAPSAKS 9606 BTO:0000938 16611631 t lperfetto Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5 SIGNOR-145999 0.47 TBK1 protein Q9UHD2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. SIGNOR-252608 0.407 LAMTOR4 protein Q0VGL1 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164778 0.926 RNF183 protein Q96D59 UNIPROT TNFRSF10B protein O14763 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31889078 t miannu RNF183 mediated K63-linked ubiquitination and lysosomal degradation of DR5. SIGNOR-272212 0.2 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 0.677 MAPK3 protein P27361 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. SIGNOR-74564 0.532 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 19789335 t gcesareni Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha. SIGNOR-188325 0.841 APBA1 protein Q02410 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 BTO:0000298 11036064 t miannu Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. SIGNOR-264038 0.667 PRKG2 protein Q13237 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser254 WTYPRKEsGRLVEPV 9606 BTO:0001007 35066967 t miannu Secretory PKG II inhibited PDGF‐BB ‐induced PDGFRβ activation via phosphorylating its Ser254. SIGNOR-277577 0.272 (-)-selegiline chemical CHEBI:9086 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 21377879 t Luana All the compounds were found as extremely potent and selective towards MAO-B, (Table 2) with at least 100 times more potent than the positive control selegiline.  SIGNOR-258136 0.8 CAMK2B protein Q13554 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-250689 0.518 AP-5 Adaptor complex complex SIGNOR-C592 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 9606 29381698 f miannu  Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. SIGNOR-280860 BMP1 protein P13497 UNIPROT COL5A2 protein P05997 UNIPROT up-regulates activity cleavage Glu1253 SEVKMDAeFRHDSGY 9606 BTO:0002974 11741999 t miannu BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro. BMP-1 efficiently cleaves pro-α2(V) C-propeptides at a single site between residues 1250 (Glu) and 1251 (Asp). SIGNOR-256343 0.607 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-216949 0.416 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101123 0.926 AKAP12 protein Q02952 UNIPROT PKC proteinfamily SIGNOR-PF53 SIGNOR up-regulates activity relocalization 14657015 t lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. SIGNOR-271838 0.459 MAPK1 protein P28482 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 22139079 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-195153 0.2 NR0B2 protein Q15466 UNIPROT ESR2 protein Q92731 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10648597 f gcesareni These novel insights provide a mechanistic explanation for the inhibitory role of shp in nuclear receptor signaling, and they may explain how shp functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor. SIGNOR-74291 0.625 NCF1 protein P14598 UNIPROT CYBA protein P13498 UNIPROT up-regulates activity binding 9606 12672956 t miannu Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase. SIGNOR-276625 0.79 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-236159 0.87 PRKCD protein Q05655 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser289 GQVLGRRsFEGRICA 9606 12097319 t llicata The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation. SIGNOR-90279 0.307 BAP1 protein Q92560 UNIPROT KEAP1 protein Q14145 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 35052618 t miannu BAP1 directly binds to and deubiquitinates KEAP1. BAP1 stabilizes KEAP1 by binding to the BTB domain. SIGNOR-268924 0.2 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 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-267508 0.8 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 0.672 ACADM protein P11310 UNIPROT trans-oct-2-enoyl-CoA(4-) smallmolecule CHEBI:62242 ChEBI up-regulates quantity chemical modification 9606 3035565 t miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  SIGNOR-280377 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AMPH protein P49418 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 15262992 t inferred from 70% family members lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-270197 0.2 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 t llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  SIGNOR-250648 0.521 acetyl-CoA smallmolecule CHEBI:15351 ChEBI (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI up-regulates quantity precursor of 29597274 t lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis SIGNOR-267651 0.8 SMARCAD1 protein Q9H4L7 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity binding 9606 21549307 t 1 miannu SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin SIGNOR-239838 0.504 CHEK2 protein O96017 UNIPROT TRIM32 protein Q13049 UNIPROT up-regulates activity phosphorylation Ser55 LEKLLASsINGVRCP 9606 BTO:0000007 37943659 t miannu We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.  SIGNOR-277790 0.2 ROS stimulus SIGNOR-ST2 SIGNOR Lipid peroxidation phenotype SIGNOR-PH235 SIGNOR up-regulates 9606 BTO:0003081 37834426 t miannu  ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell’s antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC. SIGNOR-279881 0.7 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0002181 23279204 f SARA G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs SIGNOR-260984 0.7 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation Ser82 STSQSPHsPDSSQSS -1 8650547 t miannu CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase). SIGNOR-250096 0.61 UNC13B protein O14795 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 31679900 f miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle. MUNC13 is proposed to tether synaptic vesicles by bridging between vesicle and plasma membrane via its C2C-domain and C1/C2B-domains SIGNOR-264386 0.7 MYO1E protein Q12965 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 BTO:0000848 28348210 t miannu Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer. SIGNOR-265427 0.2 SPC24 protein Q8NBT2 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-265185 0.94 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr799 PLQDGSRtPHYGSQT 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-143935 0.776 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1270 SDLPVPRtPGSGAGE 9606 10995387 t llicata Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter. SIGNOR-82137 0.447 CSNK2A1 protein P68400 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates phosphorylation Ser67 DTRKKDAsDDLDDLN 9606 BTO:0000567 16225457 t lperfetto The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals. SIGNOR-141051 0.35 PRKD1 protein Q15139 UNIPROT DYNLL1 protein P63167 UNIPROT down-regulates activity phosphorylation 9606 21087603 t miannu We now provide evidence that PKD phosphorylates an additional site in DLC1, namely serine 807 within the GAP domain, adding another layer of complexity to PKD-mediated negative regulation of the DLC1 tumor suppressor protein.|We previously reported that PKD inhibits DLC1 cellular function through phosphorylation of serines 327 and 431 [10]. SIGNOR-279265 0.2 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12370315 f gcesareni It has been shown that maml1 binds directly to the ankyrin repeat region of notch1 and forms a dna-binding complex with icn and csl SIGNOR-94029 0.923 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267515 0.8 VEGFD protein O43915 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 9435229 t gcesareni Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors. SIGNOR-55163 0.2 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 0.8 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 BTO:0000007 10191262 t lperfetto This is followed by the ptdins(3,4,5)p3-independent phosphorylation at thr256 that activates sgk, and is catalysed by pdk1 SIGNOR-236796 0.65 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser152 PTPAKRRsSALWSEM -1 15684429 t miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. SIGNOR-263019 0.249 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2V1 protein Q13404 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271355 0.465 IRF2 protein P14316 UNIPROT TAP1 protein Q03518 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15778351 f miannu We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. SIGNOR-254530 0.2 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 0.2 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258899 0.8 BMP2 protein P12643 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 21793042 f gcesareni Upon bmp binding to the bmpr-ii, bmpr-i is recruited to form an activated quaternary complex, which then phosphorylates and activates intracellular smad proteins. Receptor smads bind to a co-smad and translocate to the nucleus to serve as transcription factors. SIGNOR-175273 0.474 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser301 DAVLPEQsPGDFDFN 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198984 0.322 PDPK1 protein O15530 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates phosphorylation Thr774 GYGDRTStFCGTPEF 9606 10753910 t miannu It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively) SIGNOR-76640 0.567 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 0.36 ARHGDIA protein P52565 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity guanine nucleotide exchange factor 10116 BTO:0000526 20696765 t miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma. SIGNOR-268436 0.811 SRC protein P12931 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Tyr68 GQTVDDPyATFVKML 9606 19802004 t lperfetto Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway SIGNOR-188352 0.553 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262673 0.2 MRPS21 protein P82921 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261486 0.672 IKBKG protein Q9Y6K9 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 14695475 t Barakat Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation. SIGNOR-274149 0.827 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Thr185 HDHTGFLtEYVATRW 9606 11971971 t gcesareni Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-86709 0.744 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 17151142 t These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253592 0.93 apixaban chemical CHEBI:72296 ChEBI F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189865 0.8 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser698 PEWPRRAsCTSSTSG -1 196939 t The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation SIGNOR-253009 0.508 PTPRJ protein Q12913 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr813 NSLFTPDyELLTEND 9606 28912580 t miannu These results support PTPRJ preferentially dephosphorylating Y813 and Y868 in JAK2.|We revealed that PTPRJ negatively regulates leptin signaling by dephosphorylating specific tyrosine residues (Y813 and Y868) in JAK2, the simultaneous phosphorylation of which plays a pivotal role in JAK2 activation. SIGNOR-277093 0.323 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 0.397 SREBF1 protein P36956 UNIPROT FASN protein P49327 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-142294 0.495 FOXO1 protein Q12778 UNIPROT 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-68152 0.377 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15864272 t gcesareni The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 SIGNOR-135955 0.714 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 0.8 EEF1A2 protein Q05639 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 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-269526 0.8 GARS1 protein P41250 UNIPROT AMP smallmolecule CHEBI:456215 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-270481 0.8 IL22RA1 protein Q8N6P7 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 12087100 t gcesareni Il-22 activates jak1 and tyk2 SIGNOR-90165 0.542 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198126 0.269 CDKN2A protein Q8N726 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.788 STK38 protein Q15208 UNIPROT AAK1 protein Q2M2I8 UNIPROT up-regulates activity phosphorylation Ser637 AGHRRILsDVTHSAV 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. AAK1 phosphorylation regulates dendrite branching and length SIGNOR-263034 0.27 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG1 protein Q92886 UNIPROT up-regulates quantity by expression 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-254632 0.249 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 9606 BTO:0000567 20682768 t lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva SIGNOR-167340 0.39 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001573 17671177 t gcesareni Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin. SIGNOR-157162 0.49 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17548358 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-155381 0.332 PDGFRA protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 f To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation. SIGNOR-254377 0.324 NOTCH1 protein P46531 UNIPROT TCF12 protein Q99081 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22577461 f miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. SIGNOR-197514 0.365 MAPK3 protein P27361 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. Erk catalyzes the phosphorylation more efficiently than jnk SIGNOR-91063 0.352 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 t miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. SIGNOR-277801 0.2 ACTB protein P60709 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-270757 0.527 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 0.42 PTEN protein P60484 UNIPROT NR5A1 protein Q13285 UNIPROT down-regulates activity dephosphorylation 9606 27838257 t miannu The fact that SF-1 and PIP3 is robustly dephosphorylated by PTEN, yet SF-1 and PIP2 is resistant to phosphorylation by p110 PI3-kinases, suggests that nuclear proteins like SF-1 can help decouple PTEN signaling in the nucleus from p110 signaling.|We also showed that PTEN can dephosphorylate the SF-1 and PIP3 product of the IPMK reaction, and that PTEN inhibits SF-1 transcriptional activity. SIGNOR-277117 0.256 TP53 protein P04637 UNIPROT DRAM2 protein Q6UX65 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-259148 0.306 PRKACA protein P17612 UNIPROT PPP1R9B protein Q96SB3 UNIPROT down-regulates activity phosphorylation Ser94 SERGVRLsLPRASSL 9606 BTO:0000007 12417592 t miannu Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged. SIGNOR-250035 0.31 SIK2 protein Q9H0K1 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser91 ENLKKSLsCANLSTF 9606 24561619 t lperfetto Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion SIGNOR-204648 0.331 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB5 protein Q9Y5G0 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-265714 0.2 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Thr282 RGKEGPGtPTRSSVI 9606 BTO:0001271 18246121 t llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. SIGNOR-160630 0.282 LETM1 protein O95202 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains. SIGNOR-262545 0.7 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109621 0.686 FOXF1 protein Q12946 UNIPROT GH2 protein P01242 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16772323 f miannu Overexpression of FOXF1 in BeWo and HepG2 cells induced the GHV promoter, whereas overexpression of FOXF2 was without effect. These studies indicate that FOXF1 induces GHV expression by interaction with a FOXF1/FOXF2 cis-element in the proximal promoter. SIGNOR-254175 0.2 IRAK1 protein P51617 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 15465816 t gcesareni Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation. SIGNOR-129685 0.55 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-244727 0.2 F2 protein P00734 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates binding 9606 BTO:0001253 11356985 t gcesareni Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2. SIGNOR-108183 0.611 GADL1 protein Q6ZQY3 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267546 0.8 YY1 protein P25490 UNIPROT SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR form complex binding 10090 20887952 t lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. SIGNOR-235580 0.2 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI2 protein P10070 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni Both molecules gant58 and gant61 were capable of interfering with gli1 as well as gli2-mediated transcription in a dose-dependent manner SIGNOR-188866 0.8 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 0.831 PTGS2 protein P35354 UNIPROT episterol ester smallmolecule CHEBI:52393 ChEBI down-regulates quantity chemical modification 9606 19126760 t miannu After biosynthesis, 2-AG is partially degraded by postsynaptic COX-2, and partly released to the extracellular space.¬† SIGNOR-264270 0.8 EGR1 protein P18146 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003336 29212876 t miannu Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC. SIGNOR-263508 0.62 YES1 protein P07947 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation 9606 BTO:0002181 26198631 t miannu YY1 phosphorylation is mediated by Src family kinases. SIGNOR-276941 0.2 PKLR protein P30613 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266535 0.8 TP53 protein P04637 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19879762 t lperfetto As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5. SIGNOR-209687 0.26 CSNK2A1 protein P68400 UNIPROT CASP2 protein P42575 UNIPROT down-regulates phosphorylation Ser157 LYKKLRLsTDTVEHS 9606 16193064 t gcesareni Here we show that protein kinase (pk) ck2 phosphorylates procaspase-2 directly at serine-157. When intracellular pkck2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a piddosome-independent manner. SIGNOR-140836 0.309 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Thr372 STRIRQNtRDHPSTA 9606 BTO:0000671 10908300 t gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. SIGNOR-79686 0.2 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191277 0.8 naloxone chemical CHEBI:7459 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 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-258661 0.8 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 20708153 t lperfetto Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation SIGNOR-167488 0.321 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 0.5 CYP17A1 protein P05093 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268654 0.8 FYN protein P06241 UNIPROT TOM1L1 protein O75674 UNIPROT up-regulates activity phosphorylation Tyr460 AVTTEAIyEEIDAHQ -1 11711534 t Tyr-457, located in the presumed Src SH2 binding site, is the predominant tyrosine residue that is phosphorylated by Fyn.Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells. SIGNOR-251185 0.434 KIF7 protein Q2M1P5 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by stabilization binding 9606 19549984 t lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. SIGNOR-209611 0.586 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 24942200 t flangone During neural fate specification, nuclear translocation of ERK1/2 is critical for its activation of Sox2 transcription. More-over, melatonin-induced Sox2 expression, through ERK1/ 2 activation, could locate between base pairs2719 and 1708 in the mouse Sox2 gene. SIGNOR-241977 0.2 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates activity phosphorylation Ser337 ASGTLPVsQPKSWAS 9606 35627217 t lperfetto As shown, both AKT and ATM increase the activity of USP10.|Yuan et al. demonstrated that ATM could phosphorylate USP10 at Thr42 and Ser337 upon the DNA-damage response and USP10 was translocated into the nucleus, where the N-terminus of USP10 (amino acids 1\u2013100) binds to p53 and inhibits its ubiquitination [27]. SIGNOR-279796 0.252 MARS1 protein P56192 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-270352 0.2 ATRX protein P46100 UNIPROT ZBED1 protein O96006 UNIPROT up-regulates activity binding 7227 BTO:0001138 22021382 t 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. SIGNOR-239729 0.413 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257911 0.8 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates phosphorylation Ser394 EDAVHEDsGDEDGED 9606 12082111 t gcesareni Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation. SIGNOR-89937 0.619 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser853 IAEPMRRsVSEAALA 10090 BTO:0000944 11581251 t lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme SIGNOR-249202 0.602 MAPK8 protein P45983 UNIPROT CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser103 ESSLSSEsSESSDAG 9606 BTO:0000567 21807946 t miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). SIGNOR-276351 0.284 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 BTO:0000671 15694384 t llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. SIGNOR-133837 0.2 COX7C protein P15954 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267754 0.779 VAV1 protein P15498 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000725 9151714 t Barakat In summary, we demonstrate here that Y315 in ZAP-70 is required to interact with the Vav SH2 domain, and is critical for ZAP-70–mediated gene activation. SIGNOR-274150 0.838 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 0.2 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 0.496 CSNK2A1 protein P68400 UNIPROT APEX1 protein P27695 UNIPROT up-regulates activity phosphorylation Ser123 HQYWSAPsDKEGYSG 9534 BTO:0004055 10023679 t llicata Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1. SIGNOR-250825 0.485 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CELF6 protein Q96J87 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 31534127 t miannu CELF6 is degraded by ubiquitin-dependent proteasome pathway. The cell cycle-dependent expression of CELF6 is mediated through the ubiquitin-proteasome pathway, SCF-β-TrCP recognizes a nonphospho motif in CELF6 and regulates its proteasomal degradation. SIGNOR-269043 0.2 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 0.42 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 0.579 MAP2K3 protein P46734 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273950 0.607 GNAL protein P38405 UNIPROT ADCY3 protein O60266 UNIPROT up-regulates activity binding 9606 BTO:0004345 23817016 t Marta Tosoni Subsequently, the Gaolf subunit activates the integral membrane protein adenylyl cyclase type III (AC3), leading to the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP) SIGNOR-278072 0.641 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 ASAAGGLsPVTNLTV 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277340 0.652 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 15621017 t Thus, the increased immunoreactivity of CaMKII-α of the remaining neurons may be the consequence of the altered calcium dynamics in neurons. There is evidence indicating that CaMKII might participate in tau phosphorylation in AD. SIGNOR-255490 0.596 PRDM16 protein Q9HAZ2 UNIPROT SKI protein P12755 UNIPROT up-regulates binding 9606 19049980 t miannu Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes. SIGNOR-182529 0.326 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser244 GTHYSVQsDIWSMGL 9606 8131746 t gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf SIGNOR-36453 0.574 MAPK1 protein P28482 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity SIGNOR-48338 0.6 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser441 GHSPLSLsAQSVMEE 9606 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204736 0.548 ATR protein Q13535 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 22735644 t lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  SIGNOR-267662 0.438 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 0.2 cetirizine chemical CHEBI:3561 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258868 0.8 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 0.448 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 0.2 PAK6 protein Q9NQU5 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by destabilization phosphorylation Ser579 YGALTCGsCKVFFKR 9606 23132866 t miannu Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli. SIGNOR-279247 0.2 PDK1 protein Q15118 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation 9606 15068796 t miannu Since both AKT-1, AKT-2, and SGK-1 are phosphorylated by PDK-1 and are themselves capable of phosphorylating DAF-16, their direct contact may reflect a temporary, regulatory interaction.|This demonstrates that functional PDK-1 is required to activate AKT-1, AKT-2, and SGK-1 in vivo. SIGNOR-279248 0.375 PAMPs stimulus SIGNOR-ST11 SIGNOR MBL2 protein P11226 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-263405 0.7 CCND3 protein P30281 UNIPROT CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR form complex binding 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-273027 0.935 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 0.864 DYRK1A protein Q13627 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser409 LSPTSYMsPTLPALD 9606 28235034 t miannu DYRK1A phosphorylation of NFATc1 and alphaA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation.|Here, we demonstrated that DYRK1A increased NFATc1 (NFATc1 and alphaA isoform) protein stability, in contrast to the decrease of NFATc2 protein stability by DYRK1A. SIGNOR-278276 0.429 MKRN1 protein Q9UHC7 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26183061 t miannu EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase.|In fact, epidermal growth factor-stimulated pAKT phosphorylates and subsequently stabilizes MKRN1, which then ubiquitinates and induces the degradation of PTEN. SIGNOR-278830 0.43 RPS6KA1 protein Q15418 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates activity phosphorylation 9606 25106868 t miannu These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the Messenger RNA destabilization activity of ZFP36L1.|These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the mRNA destabilization activity of ZFP36L1. SIGNOR-279280 0.2 SGK3 protein Q96BR1 UNIPROT NDRG1 protein Q92597 UNIPROT down-regulates activity phosphorylation 9606 25458846 t miannu It has been shown that SGK3 phosphorylation of NDRG1 primes for subsequent phosphorylation by GSK-3beta.|Since NDRG1 is a direct SGK substrate, this correlation suggests that SGK3 activation and signaling may modulate NDRG1 degradation. SIGNOR-279282 0.402 L-arginine chemical CHEBI:16467 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 f Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. SIGNOR-268018 0.8 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248313 0.498 KIFC1 protein Q9BW19 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 BTO:0000948 33361741 t miannu We found that KIFC1 could directly bind to CENPE in SKOV3 cells (Figure 4C, 4D). SIGNOR-266116 0.573 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 BTO:0000782 15326477 t lperfetto P38sapk2 phosphorylates cyclin d3 at thr-283 and targets it for proteasomal degradation SIGNOR-128402 0.2 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1197 STAENAEyLRVAPQS 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-248723 0.617 KAT2A protein Q92830 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-269598 0.2 DDX21 protein Q9NR30 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260192 0.266 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 0.265 CTDSPL2 protein Q05D32 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 20932329 f Indirect:regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. SIGNOR-251777 0.2 ATM protein Q13315 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation 9606 22976441 t miannu These results elucidated the specificity of this in vivo degradation assay, and further implicated that CKI\u03b4-dependent phosphorylation events is the major signaling route through which DNA damage-dependent activation of ATM might control timely turnover of Mdm2 during genotoxic stress. (A) ATM-mediated phosphorylation of CK1\u03b4 promotes CK1\u03b4 nuclear localization.|We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKI\u03b4 at two well-conserved S/TQ sites, which promotes CKI\u03b4 nuclear localization to increase CKI\u03b4-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCF\u03b2-TRCP. SIGNOR-279504 0.34 PDGFRB protein P09619 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr635 PLPPPPAyDDVAQDE 9606 BTO:0002036 25257795 t miannu  Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT.  SIGNOR-276854 0.359 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8962164 f irozzo These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. SIGNOR-256279 0.487 EFNA2 protein O43921 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. SIGNOR-52206 0.806 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 0.8 PPM1D protein O15297 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity dephosphorylation Thr543 IDEDGENtQIEDTEP 9606 31619012 t miannu In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. SIGNOR-277046 0.392 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 19115199 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-182988 0.748 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 0.617 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 LDILHNSsQMKSMST 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265230 0.588 BRCA1-BARD1 complex complex SIGNOR-C297 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-263222 0.845 BMX protein P51813 UNIPROT F2R protein P25116 UNIPROT down-regulates activity phosphorylation Tyr383 SECQRYVySILCCKE 9606 31910739 t miannu As shown in xref \u2013 xref , BMX overexpression increased PAR1-WT phosphorylation but had no effect on PAR1 Y 381 FY 383 F mutant, indicating that BMX phosphorylated PAR1 at Y 381 and Y 383 .|Mechanically , BMX represses PAR1 signaling in ECs by promoting PAR1 phosphorylation and internalization . SIGNOR-279594 0.2 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 0.8 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.914 PIR protein O00625 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity binding 9606 BTO:0003081 33373853 t miannu In contrast, the depletion of PIR initiates HMGB1-dependent autophagy by binding to BECN1, and subsequently promotes ferroptosis by activating ACSL4.  SIGNOR-279852 0.2 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr239 VPEMPGEtPPLSPID 9606 1846781 t lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. SIGNOR-21784 0.331 HMGCS1 protein Q01581 UNIPROT Ferroptosis phenotype SIGNOR-PH234 SIGNOR down-regulates 9606 BTO:0000192 36702290 f miannu In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. SIGNOR-279855 0.7 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 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-257969 0.8 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 0.46 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 0.7 CDKN2A protein P42771 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 10022885 t gcesareni However, induction of p16(ink4a) also causes marked inhibition of cdk2 activity. SIGNOR-64431 0.48 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90521 0.793 SPEG protein Q15772 UNIPROT JPH2 protein Q9BR39 UNIPROT up-regulates activity phosphorylation 9606 27729468 t miannuccelli Studies in HEK293 cells confirmed that SPEG overexpression increases JPH2 phosphorylation . SIGNOR-279759 0.36 SRC protein P12931 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates quantity phosphorylation Tyr216 IPTSPTPyTYNKSCD 9606 26042227 t miannuccelli These data strongly suggest that PRAK phosphorylation by Src on Y188 and Y216 drives the relocalization of PRAK to focal adhesion structures during cell adhesion. SIGNOR-279762 0.372 PP121 chemical CHEBI:50915 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206292 0.8 TFE3 protein P19532 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto We found a TFE3-dependent increase in the amount of FLCN in ARPE-19 cells starved of nutrients for 24 hours (Fig. 3E). Accordingly, we found that overexpression of TFE3 in ARPE-19 cells resulted in an increase in FLCN protein abundance (Fig. 3F), as well as the mRNA abundance of FLCN and two FLCN-interacting proteins, FNIP1 and FNIP2 (Fig. 3G) (32). SIGNOR-276819 0.445 COPS4 protein Q9BT78 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270762 0.939 COX6B1 protein P14854 UNIPROT Cytochrome c oxidase-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-267742 0.756 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 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-201530 0.96 PRKACB protein P22694 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-267412 0.325 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-55701 0.926 CEBPA protein P49715 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 11283671 f apalma We previously reported that the transcription factor C/EBPα is sufficient to induce granulocytic differentiation in multipotential precursor cells, and that Cebpa -knockout mice have a selective block in granulocyte maturation SIGNOR-255674 0.7 SCF-FBW7 complex SIGNOR-C135 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276912 0.275 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-270297 0.653 AMPK complex SIGNOR-C15 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 f lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. SIGNOR-209929 0.7 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259234 0.8 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression 9606 BTO:0001103;BTO:0002314 22493066 f gcesareni We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk. SIGNOR-254343 0.2 MTR protein Q99707 UNIPROT homocysteine smallmolecule CHEBI:17230 ChEBI down-regulates quantity chemical modification 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253142 0.8 LRRC4 protein Q9HBW1 UNIPROT CDK4 protein P11802 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264059 0.2 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 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-248716 0.709 RNF41 protein Q9H4P4 UNIPROT VPS52 protein Q8N1B4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28542518 t miannu RNF41 ubiquitinates and relocates VPS52 away from VPS53, another shared subunit of the GARP and EARP complexes, towards RNF41-positive structures. SIGNOR-278597 0.433 PTPN1 protein P18031 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 23639442 t lperfetto This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y 1175 , the site involved in activating ERK signaling. SIGNOR-277011 0.418 NPTX1 protein Q15818 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity binding 10090 BTO:0000938 15115814 t inferred from family member lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. SIGNOR-270235 0.335 HDAC2 protein Q92769 UNIPROT ZNF318 protein Q5VUA4 UNIPROT up-regulates activity binding 9606 BTO:0001321 16469430 t Monia A central domain of TZF is required for repression of AR-mediated transactivation. The results revealed that HDAC2 was coimmunoprecipitated with TZF (Fig. 6A), These results indicate that AR, TZF and HDAC2 form a ternary complex during the repression of AR-mediated transactivation. SIGNOR-261188 0.329 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 0.7 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 0.2 CSNK2A2 protein P19784 UNIPROT SUZ12 protein Q15022 UNIPROT up-regulates activity phosphorylation Ser583 PQEMEVDsEDEKDPE 9606 BTO:0002181 36351927 t miannu CK2 is the kinase for the phosphorylation of S583 of SUZ12. SIGNOR-277797 0.2 TACR3 protein P29371 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-257267 0.452 KCNQ2 protein O43526 UNIPROT KCNQ3 protein O43525 UNIPROT up-regulates activity binding 10116 BTO:0000938 9836639 t The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. SIGNOR-268833 0.515 TPI1 protein P60174 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI down-regulates quantity chemical modification 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-266491 0.8 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT up-regulates activity phosphorylation Thr495 SATGKRQtCDIEGLV -1 12534294 t miannu RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP SIGNOR-250046 0.338 ARID1B protein Q8NFD5 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271437 0.336 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 0.754 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 0.246 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Thr220 QSNYIPEtPPPGYIS 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-248794 0.515 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 0.46 NELFE protein P18615 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271400 0.904 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 0.7 D-fructofuranose 6-phosphate(2-) smallmolecule CHEBI:61527 ChEBI 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) smallmolecule CHEBI:58725 ChEBI up-regulates quantity precursor of 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-268098 0.8 SLC24A1 protein O60721 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264390 0.8 SAGA complex complex SIGNOR-C465 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269637 0.2 MAPK14 protein Q16539 UNIPROT JDP2 protein Q8WYK2 UNIPROT unknown phosphorylation Thr148 VRTDSVKtPESEGNP -1 12225289 t miannu Wild-type JDP2 exhibited efficient phosphorylation by the p38 kinase, the mutant JDP2 T%)A did not incorporate labelled Figure 5 JDP2 C-terminal domain is necessary but not sufficient for p38 phosphorylation (A) p38 phosphorylated JDP2 at Thr-148. Bacterially purified His-JDP2 (Wt) or His-JDP2 T148A (Ala) were incubated with bacterially purified activated p38 F327S [21] in the presence of [γ- 32P]ATP for 30 min. Proteins were resolved by SDS/PAGE (12 % gel), dried and exposed to autoradiography. (B) The JDP2 C-terminal domain is necessary but not sufficient for phosphorylation by p38 kinase. Bacterially purified GST fusion proteins with full-length JDP2 (Wt) C-terminally truncated JDP2 (∆C) and JDP2 C-terminal fragment (Dock) were used in an in vitro kinase assay as described in (A). A representative experiment is presented. (C) In vitro kinase assay using GST-JDP2 (JDP2wt), JDP2 ∆C and JDP2-Dock as substrates with either activated p38 or HA-JNK2 kinases. Protein mixtures were resolved by SDS/PAGE, fixed, dried and analysed by PhosphorImaging. The results represent meansS.E.M. from three independent experiments. phosphate in the presence of activated p38 kinase. This indicates that both p38 and JNK kinases are able to integrate stress signals to JDP2 Thr-148 SIGNOR-250100 0.38 EGFR protein P00533 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266335 0.382 MAPK3 protein P27361 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Thr693 RELVEPLtPSGEAPN 9606 1651322 t lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. SIGNOR-20549 0.557 MYBL2 protein P10244 UNIPROT CLU protein P10909 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10770937 t miannu Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA. SIGNOR-269800 0.274 ACVR2B protein Q13705 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 21966641 t areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254985 0.69 ARF6 protein P62330 UNIPROT Macropinosomes recycle phenotype SIGNOR-PH230 SIGNOR up-regulates 9606 39000072 t miannu ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane  SIGNOR-277785 0.7 KIT protein P10721 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000830 15526160 f miannu A number of studies have demonstrated the ability of SCF to activate the Ras-Erk pathway. The adapter protein Grb2 can directly associate with phosphorylated Y703 and Y936 in c-Kit SIGNOR-254947 0.304 F2RL3 protein Q96RI0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 t gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13) SIGNOR-196015 0.408 SIRT1 protein Q96EB6 UNIPROT NCOR1 protein O75376 UNIPROT up-regulates 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-253505 0.621 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP7 protein P18075 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 19896409 f lperfetto BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others. SIGNOR-248843 0.561 MED19 protein A0JLT2 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266663 0.851 PRL protein P01236 UNIPROT KRT19 protein P08727 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-251905 0.26 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr463 MLAGVSEyELPEDPR 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 SIGNOR-236179 0.2 GSK3B protein P49841 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 23685991 t miannu Invitro, both GSK3alpha and GSK3beta phosphorylate IRF3 at the linker region. SIGNOR-279182 0.346 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559 SIGNOR-277813 0.2 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 0.768 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr488 GAEDSGDtEDELRRV 9606 20471329 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair SIGNOR-165427 0.395 ATR protein Q13535 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates activity phosphorylation Ser19 GTSKCPPsQRVPALT 9606 BTO:0002181 18536714 t miannu We have also demonstrated that DNA damage triggers disruption of the HIPK2-Siah-1 complex, resulting in HIPK2 stabilization and activation. Disruption of the HIPK2-Siah-1 complex is mediated by the ATM/ATR pathway and involves ATM/ATR-dependent phosphorylation of Siah-1 at Ser 19. SIGNOR-276167 0.2 RPL34 protein P49207 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-262467 0.839 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 SIGNOR-166718 0.585 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 0.783 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252085 0.2 SRC protein P12931 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Tyr8 MAQFDTEyQRLEASY 9606 27934868 t miannu Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. SIGNOR-266367 0.342 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 0.328 STAT3 protein P40763 UNIPROT GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000099 26865625 t miannu  In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. SIGNOR-266772 0.3 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 30017632 t miannu Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5). SIGNOR-260438 0.789 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR ABL1 protein P00519 UNIPROT down-regulates phosphorylation 9606 18794806 t inferred from 70% family members 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-270219 0.2 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation Ser239 FRRGLDDsTGGTPLT 9606 BTO:0000007 12556484 t lperfetto Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did SIGNOR-249421 0.374 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser263 NVGSPLSsPLSSMKS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276108 0.35 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 0.768 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 0.543 AR protein P10275 UNIPROT ZBTB46 protein Q86UZ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 30962287 t miannu Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling. SIGNOR-277989 0.2 ZNF503 protein Q96F45 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28258171 f Monia Intriguingly, ZPO2/ZNF503 levels were higher in breast cancer samples with WT GATA3 than in those with mutated GATA3 (Fig. 1B). We found that Zpo2 down-regulated GATA3 levels, whereas shRNA-mediated Zpo2 knockdown enhanced GATA3 expression SIGNOR-261189 0.257 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 18701453 t lperfetto Gsk3_ phosphorylates eif2b_ at ser-539 (ser-535 in the rat sequence) and inactivates it SIGNOR-180022 0.579 HTR1D protein P28221 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257116 0.25 ARHGAP39 protein Q9C0H5 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-260494 0.501 NSD3 protein Q9BZ95 UNIPROT MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0002181 28205554 t irozzo Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay. SIGNOR-259200 0.2 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 0.484 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 0.2 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 0.459 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259703 0.8 (R)-noradrenaline smallmolecule CHEBI:18357 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-258898 0.8 GSK3B protein P49841 UNIPROT STMN3 protein Q9NZ72 UNIPROT up-regulates activity phosphorylation Ser60 SFEVILKsPSDLSPE -1 22577147 t lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta SIGNOR-264882 0.264 CHEK2 protein O96017 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation 9606 22558186 t gcesareni In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk. SIGNOR-197281 0.286 EFNB3 protein Q15768 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52621 0.838 PPP3CC protein P48454 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-251735 0.2 HECTD1 protein Q9ULT8 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22431752 t Monia We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway. SIGNOR-261199 0.2 ADRA1B protein P35368 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256950 0.278 GRK5 protein P34947 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE -1 10852916 t GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5 SIGNOR-251203 0.321 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 t lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. SIGNOR-103250 0.457 SMARCD1 protein Q96GM5 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-270615 0.812 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity dephosphorylation Tyr1172 ISLDNPDyQQDFFPK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254700 0.481 FBXW11 protein Q9UKB1 UNIPROT SKP1 protein P63208 UNIPROT up-regulates binding 9606 10023660 t gcesareni The scf is composed of skp1, cdc53/cul1, and a specificity-conferring f-box protein. F-box proteins contain two domains, an f-box motif that binds skp1 and allows assembly into skp1/cdc53 complexes, and a second proteinprotein interaction domain that interacts specifically with one or more target proteins. Cdc53/cul1, in turn, interacts with both the e2 and the skp1/f-box protein complex. SIGNOR-64505 0.801 BMPR1B protein O00238 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-187190 0.643 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 0.2 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 18508628 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes. SIGNOR-178704 0.2 SLBP protein Q14493 UNIPROT H2BC11 protein P06899 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-265381 0.2 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase SIGNOR-250321 0.498 ADSL protein P30566 UNIPROT 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266608 0.8 TRIM68 protein Q6AZZ1 UNIPROT TFG protein Q92734 UNIPROT down-regulates quantity ubiquitination 9606 24999993 t miannu Having shown that TFG positively influences IFN-\u03b2 production and TRIM68 promotes ubiquitination and degradation of TFG, we next set out to determine whether this ubiquitination was involved in the inhibition of IFN-\u03b2 signalling.|Our results suggest that TRIM68 degrades TFG at a point of pathway convergence in which downstream events lead to the activation of both NF-kappaB and IRF3. SIGNOR-278738 0.451 NUMA1 protein Q14980 UNIPROT TUBB2A protein Q13885 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116936 0.2 PAK1 protein Q13153 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 12560069 t miannu Pak1 efficiently phosphorylated GST-FKHR. SIGNOR-279242 0.358 CCR4-NOT complex complex SIGNOR-C439 SIGNOR RC3H2 protein Q9HBD1 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-268353 0.315 regorafenib chemical CHEBI:68647 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259206 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-265952 0.2 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-244798 0.2 MAPK3 protein P27361 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 t lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity SIGNOR-164231 0.267 TIMM10 protein P62072 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267703 0.714 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr832 LRYEGRVyHYRINTA 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260814 0.2 DSCAML1 protein Q8TD84 UNIPROT AQP9 protein O43315 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264280 0.2 CTDSP1 protein Q9GZU7 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity dephosphorylation 9606 32764831 t miannu CTDSP1 activates DNA-PKcs and enhances DNA-PKcs dependent topoI degradation in response to irinotecan .|Our novel finding indicates that CTDSP1 dephosphorylates DNA-PKcs, changes its kinase activity, and regulates irinotecan-induced topoI degradation. SIGNOR-277101 0.2 GATA2 protein P23769 UNIPROT TRH protein P20396 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000318 33201916 t scontino The rat prepro-TRH gene is activated by GATA2. SIGNOR-267259 0.263 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 0.786 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT unknown dephosphorylation 9606 11259588 t Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation SIGNOR-248706 0.369 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 0.25 RNF41 protein Q9H4P4 UNIPROT USP8 protein P40818 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 23750007 t irozzo RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels. SIGNOR-259106 0.88 AKT1 protein P31749 UNIPROT PAWR protein Q96IZ0 UNIPROT down-regulates activity phosphorylation 9606 21555373 t miannu Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy SIGNOR-279668 0.39 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 0.558 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 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252741 0.765 EEF1A1 protein P68104 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269510 0.8 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 0.72 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 0.506 GNG12 protein Q9UBI6 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 t gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. SIGNOR-152615 0.4 PRKD1 protein Q15139 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates activity phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 20940406 t lperfetto Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba. SIGNOR-168537 0.466 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKL protein P17858 UNIPROT down-regulates activity phosphorylation -1 28607489 t miannu In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4). SIGNOR-276451 0.2 AKT1 protein P31749 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t miannu We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh. SIGNOR-252501 0.394 COL4A6 protein Q14031 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-253246 0.446 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0000567 7635160 t llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated. SIGNOR-30252 0.525 APRT protein P07741 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 15196008 t miannu In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP) SIGNOR-280465 0.8 PRKACB protein P22694 UNIPROT NGFR protein P08138 UNIPROT up-regulates phosphorylation Ser303 PEGEKLHsDSGISVD 9606 BTO:0000938 12682012 t llicata Pka phosphorylates the p75 receptor and regulates its localization to lipid rafts. activation of camp?PKA Is required for translocation of p75ntr to lipid rafts, and for biochemical and biological activities of p75ntr, such as inactivation of rho and the neurite outgrowth. SIGNOR-99755 0.625 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 0.8 SEMA5A protein Q13591 UNIPROT PLXNB3 protein Q9ULL4 UNIPROT up-regulates activity binding 10090 BTO:0000944 15218527 t miannu Plexin-B3 is a functional receptor for semaphorin 5A. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells). SIGNOR-268373 0.623 SPI1 protein P17947 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 f miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation SIGNOR-256039 0.306 TP53 protein P04637 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 28073943 t miannu KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter. SIGNOR-263729 0.281 GSK3B protein P49841 UNIPROT USF2 protein Q15853 UNIPROT up-regulates activity phosphorylation Thr230 PKIDGTRtPRDERRR 9606 25238393 t miannu Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.|Together, these data show that there are two residues within USF2, namely S155 and T230, which can be phosphorylated by GSK3beta. SIGNOR-278158 0.283 KATNA1 protein O75449 UNIPROT KATNB1 protein Q9BVA0 UNIPROT up-regulates activity binding 9606 BTO:0000567 10751153 t miannu In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer SIGNOR-267174 0.753 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation Ser44 RLQERRGsNVALMLD 9606 10559944 t llicata Here we show that cyclic-amp-dependent protein kinase (pka) phosphorylates serine residue 23 in the kim of heptp in vitro and in intact cells. This modification reduces binding of map kinases to the kim, an effect that is prevented by mutation of serine 23 to alanine. SIGNOR-72147 0.361 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1 protein P68104 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269387 0.922 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI guanosine 5'-monophosphate(2-) smallmolecule CHEBI:58115 ChEBI up-regulates quantity precursor of 9606 10338013 t miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280474 0.8 HPRT1 protein P00492 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 10338013 t miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280475 0.8 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-51284 0.458 AMPD2 protein Q01433 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification 9606 26321268 t miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280485 0.8 AMPD2 protein Q01433 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 26321268 t miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280486 0.8 AMPD2 protein Q01433 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI up-regulates quantity chemical modification 9606 26321268 t miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280488 0.8 HBEGF protein Q99075 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 14967450 t Heparin-binding EGF-like growth factor??is synthesized as a membrane-anchored mitogenic and chemotactic glycoprotein. gcesareni 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-121977 0.768 AMPD3 protein Q01432 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 26321268 t miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280491 0.8 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 16829981 t gcesareni Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow. SIGNOR-147841 0.572 VPS33B protein Q9H267 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-261830 0.756 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 0.8 SDC3 protein O75056 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 10090 BTO:0002314 20696709 t gcesareni Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. SIGNOR-254329 0.382 FAM20C protein Q8IXL6 UNIPROT VWF protein P04275 UNIPROT up-regulates activity phosphorylation 9606 30864273 t miannu In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion. SIGNOR-279331 0.2 ECHS1 protein P30084 UNIPROT trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI down-regulates quantity chemical modification 9606 40804397 t miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. SIGNOR-280366 0.8 ECHS1 protein P30084 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 40804397 t miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. SIGNOR-280367 0.8 RUNX3 protein Q13761 UNIPROT TXN2 protein Q99757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255093 0.2 EGFR protein P00533 UNIPROT KCNJ4 protein P48050 UNIPROT up-regulates activity phosphorylation Tyr234 YMTQEGEyLPLDQRD -1 21486282 t miannu These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K(IR) 2.3 channel via phosphorylation of the Y234 residue of the WT protein.  SIGNOR-276322 0.2 ECHS1 protein P30084 UNIPROT (S)-3-hydroxydecanoyl-CoA smallmolecule CHEBI:28325 ChEBI up-regulates quantity chemical modification 9606 40804397 t miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. SIGNOR-280368 0.8 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 0.637 trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI (S)-3-hydroxydecanoyl-CoA smallmolecule CHEBI:28325 ChEBI up-regulates quantity precursor of 9606 40804397 t miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. SIGNOR-280369 0.8 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 0.405 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 0.2 CBL protein P22681 UNIPROT FRS2 protein Q8WU20 UNIPROT down-regulates ubiquitination 9606 11997436 t lperfetto The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains. SIGNOR-87166 0.576 TAF10 protein Q12962 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269581 0.775 BAG1 protein Q99933 UNIPROT PPP1R15A protein O75807 UNIPROT down-regulates activity 9606 BTO:0000038 12724406 t lperfetto Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.|BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress. SIGNOR-254117 0.444 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248518 0.408 bortezomib chemical CHEBI:52717 ChEBI PSMB5 protein P28074 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000567 19428245 t Luana MG-132, which was one of the first synthetic inhibitors, interacts reversibly with the N-terminal threonine residue of the β5 active site. SIGNOR-257820 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR NLRP3 protein Q96P20 UNIPROT down-regulates activity phosphorylation Ser295 HKIVRKPsRILFLMD -1 27548431 t miannu PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. SIGNOR-277274 0.2 PIM2 protein Q9P1W9 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser467 LQLYQVDsRTYLLDF 9606 BTO:0001555 31358902 t miannu Specifically, we found that PIM2 bound to AMPKα1, and directly phosphorylated it on Thr467. Phosphorylation of AMPKα1 by PIM2 led to decreasing AMPKα1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth. SIGNOR-277471 0.2 GZMA protein P12544 UNIPROT SET protein Q01105 UNIPROT down-regulates cleavage 9606 11555662 t miannu Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity. SIGNOR-110462 0.711 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 0.353 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276085 0.278 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 0.8 UBE3A protein Q05086 UNIPROT EEF1E1 protein O43324 UNIPROT down-regulates quantity ubiquitination 9606 30020076 t miannu These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling. SIGNOR-278680 0.2 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 0.8 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 0.25 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates activity chemical activation 10116 10617617 t We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation. SIGNOR-261142 0.8 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 t irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. SIGNOR-255706 0.8 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 0.7 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Tyr69 NESGLTEyRLVSINK -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-263564 0.583 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 0.8 PRIM1 protein P49642 UNIPROT DNA primase complex complex SIGNOR-C261 SIGNOR form complex binding -1 24043831 t lperfetto Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit. SIGNOR-261339 0.99 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16600297 t lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin SIGNOR-145837 0.699 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 0.347 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 20818436 t gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation SIGNOR-167838 0.578 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser2 sPKRIAKR -1 15014043 t miannu Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. SIGNOR-262701 0.504 COPS5 protein Q92905 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 27866850 t Barakat The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization. SIGNOR-274977 0.2 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138936 0.2 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 t miannu PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2 SIGNOR-257601 0.346 MAP3K3 protein Q99759 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates 9606 10347227 f gcesareni However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. SIGNOR-68020 0.429 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 18483407 t gcesareni We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657. SIGNOR-178648 0.309 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275948 0.2 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 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-147195 0.497 RLF protein Q13129 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220920 0.2 PARP1 protein P09874 UNIPROT POLA1 protein P09884 UNIPROT up-regulates activity binding 9606 BTO:0000567 9518481 t Federica We provide evidence that in proliferating cells: (i) PARP is physically associated with the catalytic subunit of the DNA polymerase α–primase tetramer, an association confirmed by confocal microscopy, demonstrating that both enzymes are co-localized at the nuclear periphery of HeLa cells.|(iii) PARP-deficient cells derived from PARP knock-out mice exhibited reduced DNA polymerase activity, SIGNOR-261270 0.342 ARVCF protein O00192 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-252129 0.344 SP1 protein P08047 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 f Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity SIGNOR-254270 0.2 CSNK2A1 protein P68400 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser154 FLWSPFEsLCEIGEK 9606 21209074 t lperfetto We report here that phosphorylation of cdc27, a core subunit of apc, in response to tgf- signaling can facilitate the activation of apc.we have demonstrated that casein kinase ii (ckii) is involved in the phosphorylation of cdc27 in response to tgf- signaling. SIGNOR-170872 0.378 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr266 TDSIRDEyAFLQKKY 9606 BTO:0000793 29022905 t miannu In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. SIGNOR-277328 0.26 MARK2 protein Q7KZI7 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 t lperfetto We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function SIGNOR-149583 0.344 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 0.57 FGF11 protein Q92914 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253434 0.2 LYN protein P07948 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity phosphorylation Tyr448 TILTEVNyEVSNKDD 18086677 t lperfetto The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. SIGNOR-272980 0.311 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1766 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-248814 0.855 NLGN4Y protein Q8NFZ3 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-264148 0.2 PRKG2 protein Q13237 UNIPROT HCN2 protein Q9UL51 UNIPROT down-regulates activity phosphorylation Ser668 DRIGKKNsILLHKVQ 10090 BTO:0000142 21347269 t miannu Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation.We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2-5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating. SIGNOR-263185 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 9606 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-216872 0.339 CHEK1 protein O14757 UNIPROT NEK6 protein Q9HC98 UNIPROT down-regulates activity phosphorylation -1 18728393 t miannu Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro . SIGNOR-279403 0.237 MAPK14 protein Q16539 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 9606 15817653 t llicata We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis. SIGNOR-135198 0.511 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 0.491 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 SIGNOR form complex binding 9606 16914550 t miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. SIGNOR-148895 0.2 PC protein P11498 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24363178 t miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) SIGNOR-266554 0.8 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 0.2 SOD3 protein P08294 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272271 0.8 FGFR1 protein P11362 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 9606 12270934 f lperfetto Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-244865 0.31 PPP5C protein P53041 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity dephosphorylation Ser338 RPRGQRDsSYYWEIE -1 16892053 t Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK SIGNOR-248537 0.462 DLG3 protein Q92796 UNIPROT NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266006 0.72 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248301 0.5 RPS6KA1 protein Q15418 UNIPROT SLC9A3R1 protein O14745 UNIPROT up-regulates activity phosphorylation Thr156 ELRPRLCtMKKGPSG 9606 26862730 t miannu In summary, these results demonstrate that Ras-RSK1 signaling promotes nuclear localization of EBP50.|Specifically, RSK1 phosphorylates EBP50 at threonine 156 (T156) residue in a cell cycle dependent manner, which is important for nuclear translocation of EBP50 to facilitate cellular proliferation and transformation. SIGNOR-278290 0.33 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 0.2 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 0.799 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MYC protein P01106 UNIPROT up-regulates activity phosphorylation -1 32482868 t inferred from 70% family members lperfetto ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation SIGNOR-270030 0.2 FASN protein P49327 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization 9606 BTO:0001130 18838960 f lperfetto Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer SIGNOR-242878 0.268 TFEB protein P19484 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). SIGNOR-276706 0.277 STK11 protein Q15831 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Thr211 QKDKFLQtFCGSPLY 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-122686 0.546 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser393 LTPEKGQsQGLIWDF 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276764 0.289 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 0.855 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 0.453 suprofen chemical CHEBI:9362 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-257808 0.8 TRAF6 protein Q9Y4K3 UNIPROT MYC protein P01106 UNIPROT down-regulates activity ubiquitination Lys148 K-->C 9606 35045331 t miannu We posited that TRAF6 ubiquitination of MYC at K148 prevents its acetylation, which results in diminished MYC activity ( xref ). SIGNOR-278563 0.344 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 t acerquone Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation. SIGNOR-252597 0.779 DUSP23 protein Q9BVJ7 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser322 NYPFPLTsWPCSFSP 9606 20855292 t lperfetto DUSP23 prevents GCM1 from ubiquitination and prolongs the half-life of GCM1.|Second, DUSP23 is able to dephosphorylate Ser322 in GCM1 in vitro and in a stable cell line expressing HA-GCM1. SIGNOR-276982 0.464 PICK1 protein Q9NRD5 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268178 0.802 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 0.2 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260528 0.831 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21527258 f gcesareni 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-173445 0.319 FER protein P16591 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 19339212 t miannu The Fer mediated phosphorylation of specific tyrosine residues of FAK was abolished by cotransfection of shRNA against Fer (i.e., shFer), but not by control shRNA, indicating that the phosphorylation of Tyr577, 861, or 925 of FAK in suspended cells was indeed caused by Fer. SIGNOR-279409 0.251 PPP5C protein P53041 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity dephosphorylation Ser211 PGKETNEsPWRSDLL 9606 BTO:0000093 19586900 t Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription. SIGNOR-248538 0.541 CXCL9 protein Q07325 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 t miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. SIGNOR-260970 0.782 CEBPB protein P17676 UNIPROT CREB1 protein P16220-1 UNIPROT up-regulates activity binding 9534 BTO:0000298 12773552 t miannu We conclude that C/EBP-β can directly bind to the N-terminal Q1 domain of CREB in addition to binding to the leucine zipper domain. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-β enhanced the effect, while a dominant negative C/EBP inhibited it SIGNOR-263654 0.56 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 0.332 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 0.2 herbimycin chemical CHEBI:5674 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 t gcesareni Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation. SIGNOR-113767 0.8 MED20 protein Q9H944 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266679 0.774 DDR1 protein Q08345 UNIPROT CXCL5 protein P42830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003303 34237033 f miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. SIGNOR-277731 0.2 HECTD3 protein Q5T447 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0004461 28716524 t miannu HECTD3 binds and ubiquitinates caspase-9.HECTD3 inhibits caspase-9 oligomerization and association with Apaf-1. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK. SIGNOR-272329 0.2 GRK2 protein P25098 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser1104 PRAEAEDsFL 9606 15271984 t miannu In 293 cells, GRK2 overexpression reduced PDGFRbeta/NHERF association by 60%. SIGNOR-278379 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272509 0.2 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270707 0.797 H2BC11 protein P06899 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263710 0.2 PINK1 protein Q9BXM7 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 32484300 t miannu We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. SIGNOR-279548 0.6 KIT protein P10721 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation 9606 15315962 t miannu The activated KIT in turn induces phosphorylation and activation of Cbl proteins. SIGNOR-279199 0.618 tolazoline chemical CHEBI:28502 ChEBI ADRA2C protein P18825 UNIPROT down-regulates activity chemical inhibition 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258914 0.8 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175797 0.609 CRKL protein P46109 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t HPK1 phosphorylated CrkL mainly on serine and weakly on threonine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. SIGNOR-63991 0.587 MAP3K7 protein O43318 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 30385786 t miannu TAK1 inhibits YAP activity through beta-TRCP.|Thus, our data indicate that TAK1 directly phosphorylates YAP at multiple sites.|These observations prompted us to test whether TAK1 phosphorylates YAP at S127. SIGNOR-278956 0.338 MACF1 protein Q9UPN3 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000938 16815997 f gcesareni 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-147451 0.435 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 0.2 DUSP16 protein Q9BY84 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity dephosphorylation 9606 25077541 t miannu MKP7 represses mTOR function.|These results suggest that MKP7 could directly dephosphorylate pmTOR and pPRAS40 and forming complexes with these two proteins ( xref ). SIGNOR-277067 0.274 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser576 DDDFQLRsFDQLSPL 9606 BTO:0000567 18519666 t lperfetto Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation SIGNOR-178739 0.348 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276097 0.264 PLCG2 protein P16885 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10116 BTO:0002013 29430764 f Marta Tosoni PLCγ2 induces apoptosis in rat hepatocytes in vitro. SIGNOR-278087 0.7 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 0.403 TFE3 protein P19532 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276822 0.2 SRC protein P12931 UNIPROT GAK protein O14976 UNIPROT up-regulates activity phosphorylation Tyr1149 CTQPRPNyASNFSVI -1 28135906 t miannu GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149. SIGNOR-263198 0.274 MAPKAPK5 protein Q8IW41 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity phosphorylation Ser130 LHMERVIsYEEGKAL 9606 BTO:0000007 21336308 t miannu Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.  SIGNOR-276313 0.401 HARS1 protein P12081 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 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-270490 0.8 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G3 protein O43432 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269157 0.389 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 11606413 t gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. SIGNOR-111064 0.8 OXGR1 protein Q96P68 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257155 0.385 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ 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-260840 0.2 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 0.706 MAPK7 protein Q13164 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 12048211 t gcesareni 9-cis retinoid x receptor alpha (rxr alpha) interacted with erk2 but not erk5 in intact cells, whereas ets-1 interacted preferentially with erk5. Increased phosphorylation of rxr alpha and ets-1 was detected in response to 1,25d. Activated erk2 and erk5 specifically phosphorylated rxr alpha and ets-1, respectively.Mutagenesis of ets-1 (t38a) reduced cyp24 promoter activity to levels observed with the dominant-negative mek5(a) and inhibited erk5-directed phosphorylation. Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2. SIGNOR-88666 0.42 PTK2B protein Q14289 UNIPROT ID3 protein Q02535 UNIPROT up-regulates quantity phosphorylation 9606 25090023 t miannu Taken together these findings demonstrated that Pyk2 mediates the expression of ID3 protein.|Together these findings from the combined MS+MS/MS data confirm that Flag tagged ID3 is phosphorylated by active recombinant Pyk2 kinase; and support the phospho-Tyr band that was detected at the corresponding MW ~ 13 kDA for Flag-ID3 by immunoblot. SIGNOR-278496 0.2 BCOR protein Q6W2J9 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256010 0.7 TWIST2 protein Q8WVJ9 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 19581928 f miannu we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells that constitutively express Twist, a metastatic regulator and direct transcriptional repressor of E-cadherin. SIGNOR-255536 0.441 PLK3 protein Q9H4B4 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-163270 0.2 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 23863160 f lperfetto In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209907 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252834 0.911 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 10090 BTO:0000782 15735648 t miannu Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323. SIGNOR-276031 0.489 YWHAZ protein P63104 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-252397 0.277 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 t miannu The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. SIGNOR-276326 0.256 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 0.755 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Leu38 RSSKGRSlIGKVDGT -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-263584 0.526 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 9407116 t lperfetto The src family kinase hck interacts with bcr-abl by a kinase-independent mechanism and phosphorylates the grb2-binding site of bcr SIGNOR-53964 0.2 STK3 protein Q13188 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser438 EKNYQLKsRQILGMR 9606 21076410 t lperfetto Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins SIGNOR-169539 0.244 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 0.25 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 0.859 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 0.796 PTPRB protein P23467 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19136612 t VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites SIGNOR-248441 0.454 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258649 0.8 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 0.2 SF3A2 protein Q15428 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 t miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263947 0.96 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-268218 0.2 malonyl-CoA smallmolecule CHEBI:15531 ChEBI hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity precursor of 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268090 0.8 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12950161 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitro.catalase 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-86581 0.403 STK10 protein O94804 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Tyr565 MRQGRDKyKTLRQIR 9606 28430576 t miannu Ezrin activation by LOK phosphorylation involves a PIP 2 -dependent wedge mechanism.|The specificity of kinases depends on local peptide consensus sequences, which in the case of ezrin phosphorylation by LOK involves the hydrophobic residue Y565 positioned -2 residues from T567. SIGNOR-278204 0.473 SL0101 chemical CID:10459196 PUBCHEM RPS6KA3 protein P51812 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207075 0.8 SMAD3 protein P84022 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260432 0.7 GRB10 protein Q13322 UNIPROT IGF1R protein P08069 UNIPROT down-regulates binding 9606 21659604 t gcesareni Grb10 negatively regulates growth factor signaling. It binds the insulinand insulin-like growth factor 1 (igf-1) receptors, and mice without grb10 are larger and exhibit enhanced insulin sensitivity SIGNOR-174062 0.739 LAMC1 protein P11047 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 t lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. SIGNOR-253231 0.708 FHL5 protein Q5TD97 UNIPROT CREM protein Q03060 UNIPROT up-regulates activity binding 9606 10086359 t miannu ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM. ACT is expressed coordinately with CREM in a tissue- and developmentally regulated manner. It strongly stimulates CREM transcriptional activity in yeast and mammalian cells and contains an intrinsic activation function. SIGNOR-222111 0.665 MACROD2 protein A1Z1Q3 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI up-regulates quantity chemical modification 9606 32257385 t miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins SIGNOR-269842 0.8 GALR2 protein O43603 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257226 0.288 PRKCE protein Q02156 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. SIGNOR-249258 0.261 PRKAA2 protein P54646 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 SIGNOR-C15 16959574 t gcesareni We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels. SIGNOR-149388 0.577 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition 9606 19567821 t miannu The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. SIGNOR-262225 0.8 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 f miannu The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression SIGNOR-259912 0.2 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 0.776 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). SIGNOR-259428 0.2 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 16613856 t lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation SIGNOR-227547 0.524 PREX2 protein Q70Z35 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260572 0.423 POLR2G protein P62487 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266165 0.867 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR 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-263217 0.781 CDK1 protein P06493 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C17 12676926 t gcesareni Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-99742 0.556 EGR1 protein P18146 UNIPROT COL4A2 protein P08572 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 f Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) SIGNOR-251918 0.2 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser302 TQRASRRsDSASSEP 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. SIGNOR-185291 0.2 EGLN3 protein Q9H6Z9 UNIPROT BCL2L11 protein O43521-1 UNIPROT up-regulates quantity by stabilization hydroxylation Pro67 PQGPLAPpASPGPFA 9606 31375625 t lperfetto EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues SIGNOR-262003 0.254 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr85 TRSQQQPtPVTPKKY 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-160743 0.355 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr708 NIHLEKKyVRRDSGF 9606 BTO:0001271 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127540 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. SIGNOR-247992 0.2 SMC6 protein Q96SB8 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265482 0.9 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser403 DLAHSSEsQETISSM 9606 16943424 t lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. SIGNOR-149300 0.735 HTR6 protein P50406 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257395 0.25 CSNK2B protein P67870 UNIPROT MME protein P08473 UNIPROT unknown phosphorylation Ser6 sQMDITDI 9606 BTO:0003288 8943850 t llicata Taken together, these data indicate that CD10/NEP is itself phosphorylated by CKII and that CD10/NEP co-associates with additional tyrosine phosphoproteins including lyn. SIGNOR-251078 0.375 ASXL3 protein Q9C0F0 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity binding 9606 25450400 t miannu Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. SIGNOR-266764 0.266 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT up-regulates activity phosphorylation Ser406 GPGEYSRsPTF 9606 26778126 t IR-Induced Double Phosphorylation of Abraxas C Terminus S404 and S406 Is ATM Dependent SIGNOR-255588 0.2 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 0.636 CHEK1 protein O14757 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates phosphorylation Ser331 HPWVRANsRRVLPPS 9606 17276342 t lperfetto Chk1 phosphorylates aurora-b and enhances its catalytic activity in vitro. SIGNOR-152926 0.36 GOT1 protein P17174 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267510 0.8 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser726 DTSPRHLsNVSSTGS -1 12435421 t miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly SIGNOR-250009 0.433 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 0.2 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr86 ARPLVEFyEEIKKYE 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-266306 0.2 Ub:RBR_E3 complex SIGNOR-C520 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271384 0.7 SGK1 protein O00141 UNIPROT NCSTN protein Q92542 UNIPROT down-regulates quantity by destabilization phosphorylation Ser437 FLRARNIsGVVLADH 9606 BTO:0000007 22590650 t miannu SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. SIGNOR-276415 0.337 DHX9 protein Q08211 UNIPROT NUP98 protein P52948 UNIPROT up-regulates activity binding 9606 BTO:0000007 28221134 t miannu Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription. SIGNOR-260954 0.356 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser669 EDDVLSSsSCGSNSD 9606 BTO:0002181 34216621 t miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  SIGNOR-277321 0.573 EGR1 protein P18146 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003076 9300687 f Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription. SIGNOR-254277 0.2 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 BTO:0000567 21658950 t miannu Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. SIGNOR-263138 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-71419 0.2 POLR2E protein P19388 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270923 0.2 POLR2B protein P30876 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266162 0.87 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 0.695 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR APBB1 protein O00213 UNIPROT unknown phosphorylation 9606 14697653 t inferred from 70% family members 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-270166 0.2 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 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-86680 0.34 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr315 AENSRLQtPGGGSKT 10090 BTO:0000165 12832492 t llicata We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts. SIGNOR-250670 0.547 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 0.277 AKT proteinfamily SIGNOR-PF24 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome. SIGNOR-151216 0.2 MTA1 protein Q13330 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-263854 0.819 SEC61 complex complex SIGNOR-C368 SIGNOR SEC62 protein Q99442 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-265275 0.748 USP28 protein Q96RU2 UNIPROT MYC protein P01106 UNIPROT up-regulates deubiquitination 9606 BTO:0000150 17558397 t esanto Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc. SIGNOR-155590 0.703 SMARCA4 protein P51532 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65441 0.95 IRF3 protein Q14653 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 ATF3 protein P18847 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12881527 f miannu Transcription from the ASNS (asparagine synthetase) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide evidence for a potential role of multiple predicted ATF3 isoforms in the transcriptional regulation of the ASNS gene in response to nutrient deprivation. SIGNOR-253746 0.409 ritonavir chemical CHEBI:45409 ChEBI CYP3A4 protein P08684 UNIPROT down-regulates activity chemical inhibition -1 18285471 t Luana Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A SIGNOR-257769 0.8 ADRA2A protein P08913 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-257093 0.503 CREB3L1 protein Q96BA8 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 35051932 f lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|By luciferase assays, we demonstrate that CREB3L1 may be a transcription factor regulating Oxt gene expression. By RNA immunoprecipitation assays and northern blot analysis of Oxt mRNA poly(A) tails, we have found that CAPRIN2 binds Oxt mRNA and regulates its poly(A) tail length.|To investigate transcriptional regulation of the OXT gene by CREB3L1, we performed luciferase assays using a proximal Oxt promoter region transfected in HEK293T cells. The expression of full-length CREB3L1 (CREB3L1FL) and a constitutively active CREB3L1 (CREB3L1CA) significantly increased luciferase activity by 5.4- and 3.2-fold, respectively, compared with controls SIGNOR-268555 0.2 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 0.346 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1675 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248773 0.431 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 0.571 TNPO1 protein Q92973 UNIPROT NUP153 protein P49790 UNIPROT up-regulates activity relocalization 29970603 t lperfetto TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import SIGNOR-262100 0.499 S100A8 protein P05109 UNIPROT TLR4 protein O00206 UNIPROT down-regulates activity binding 9606 28137827 t miannu Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9. SIGNOR-261921 0.534 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 16571722 t gcesareni We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli. SIGNOR-145393 0.283 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 0.8 PRKAA1 protein Q13131 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139158 0.829 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203536 0.777 SNRPC protein P09234 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-270679 0.903 CREB1 protein P16220 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 t Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-256105 0.2 CDK1 protein P06493 UNIPROT CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Thr623 FKELKFLtPVRRSRR 9606 SIGNOR-C17 19369249 t llicata Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis. SIGNOR-185317 0.288 UBE3A protein Q05086 UNIPROT SIPA1L1 protein O43166 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12036950 t miannu  the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation. SIGNOR-272608 0.365 MAPK1 protein P28482 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 t lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. SIGNOR-120566 0.352 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 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 γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. SIGNOR-209717 0.678 SLC16A2 protein P36021 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI down-regulates quantity relocalization 9606 28153798 t scontino T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland. SIGNOR-267139 0.8 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 0.635 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser193 GWDSPPAsPLQRQPS 9606 10212242 t lperfetto Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates. SIGNOR-67061 0.668 CDC14B protein O60729 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 t The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification SIGNOR-248332 0.333 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106522 0.2 GOT2 protein P00505 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-268060 0.8 HIF1A protein Q16665 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-271570 0.2 EFNA1 protein P20827 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52087 0.823 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 0.29 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser141 SRSNSDEsNFSEKLR 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276293 0.772 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 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-129402 0.557 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 0.713 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-251046 0.378 PLIN3 protein O60664 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9534 BTO:0004055 9590177 t lperfetto TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi. SIGNOR-253092 0.725 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 0.266 BLOC1S3 protein Q6QNY0 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-265934 0.715 protein P0DOX5 UNIPROT Pr3-ANCA complex SIGNOR-C475 SIGNOR form complex binding 9606 27464484 t lperfetto Although the majority of PR3-ANCAs are of the IgG isotype, the results of one study showed that PR3-ANCAs of the IgA isotype were present in up to 30% of patients with GPA SIGNOR-270594 protein P0DOX5 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR form complex binding 9606 27464484 t lperfetto Although MPO-ANCAs of the IgA isotype are sometimes found in patients with IgA nephropathy or IgA vasculitis45, isotypes other than IgG have not been reported in patients with typical AAV, with the exception of a single patient with pauci-immune crescentic glomerulonephritis SIGNOR-270595 FOXO3 protein O43524 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000944 11884591 t gcesareni Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. SIGNOR-238606 0.291 testosterone smallmolecule CHEBI:17347 ChEBI SRD5A1 protein P18405 UNIPROT up-regulates activity chemical activation 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251532 0.8 CIITA protein P33076 UNIPROT IL4 protein P05112 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000782 10946277 f We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression SIGNOR-254499 0.406 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 0.8 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 22514276 t miannu A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues. SIGNOR-197058 0.492 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 0.2 GSK3A protein P49840 UNIPROT NIFK protein Q9BYG3 UNIPROT up-regulates activity phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 t miannu The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1. SIGNOR-262697 0.2 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 0.7 FGF12 protein P61328 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253424 0.2 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 0.2 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 0.2 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR PBX3 protein P40426 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. PBX3, a member of the PBX family of TALE homeobox genes, is upregulated in both NUP98‐HOXA9–transduced adult and cord blood CD34+ cells (Table 3). SIGNOR-261504 0.2 AP1 complex SIGNOR-C154 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates activity binding 9606 BTO:0000782 15928679 t Activator protein 1 (AP1) proteins are the main transcriptional partners of NFAT during T-cell activation SIGNOR-253004 0.662 lapatinib chemical CHEBI:49603 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 t Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. SIGNOR-257901 0.8 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 0.759 Frizzled proteinfamily SIGNOR-PF11 SIGNOR 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-253124 0.2 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 0.8 DGC complex SIGNOR-C217 SIGNOR AQP4 protein P55087 UNIPROT up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626543 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265443 0.307 GSK3B protein P49841 UNIPROT KLF6 protein Q99612 UNIPROT up-regulates activity phosphorylation 9606 23085750 t miannu Functionally, GSK3beta enhanced KLF6 mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant.|These data establish that GSK3\u03b2 directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression. SIGNOR-279373 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PIN1 protein Q13526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 19151708 f lperfetto Previously, we have shown that commitment of the C2C12 cells to the osteoblastic lineage occurs around 24h after BMP treatment, when the osteoblast specific transcription factor Cbfa1 and the novel osteoblast related genes Tcf7 and Hey1 become regulated SIGNOR-254342 0.2 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 0.447 brimonidine chemical CHEBI:3175 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258901 0.8 KIRREL3 protein Q8IZU9 UNIPROT CASK protein O14936 UNIPROT up-regulates activity binding 9606 BTO:0000232 33853164 t miannu A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia. KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene.  SIGNOR-269078 0.459 ATR protein Q13535 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr859 WEVGFPStQTCMERG 9606 23273981 t llicata Characterization of this site using phospho-specific antibodies and mutational analysis reveals that it is phosphorylated by atr and is required for binding of ctip to chromatin and subsequent processive resection. SIGNOR-200245 0.615 CSNK2A1 protein P68400 UNIPROT ABCF1 protein Q8NE71 UNIPROT unknown phosphorylation Ser109 KKLSVPTsDEEDEVP 9606 17894550 t gcesareni We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2. SIGNOR-157933 0.2 PRRX1 protein P54821 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-221932 0.273 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t lperfetto Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo SIGNOR-244765 0.2 MAPK12 protein P53778 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114067 0.2 SH3RF1 protein Q7Z6J0 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates activity ubiquitination 9606 20976103 t miannu Upon TG induced ER calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the ER .|Upon thapsigargin-induced endoplasmic reticulum calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the endoplasmic reticulum . SIGNOR-278779 0.324 PRKCQ protein Q04759 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity phosphorylation Ser111 TPEGRRTsRRKRAKV 9606 29311580 t miannu Inhibiting PKC-theta also increased the H3K4 demethylase activity of LSD1, indicating that active PKC-theta may prevent LSD1 from demethylating H3K4 and subsequently causing gene repression.|PKC-theta directly phosphorylates LSD1 at serine 111 and regulates its repressive activity and nuclear localization. SIGNOR-279104 0.259 CBP/p300 complex SIGNOR-C6 SIGNOR KLF1 protein Q13351 UNIPROT up-regulates activity acetylation 9606 BTO:0002731 9707565 t Regulation miannu CBP and p300, but Not P/CAF, Enhance EKLF Trans-activation in Erythroid Cells. We find that EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region. SIGNOR-251789 0.46 TLR5 protein O60602 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24709011 f miannu These studies demonstrate a novel function of Toll-like receptor-5 (TLR5) in a human multiple myeloma (MM) cell line, KMS28BM. These cells express high levels of both TLR5 mRNA and protein. When cells were treated with the specific TLR5 ligand flagellin, proliferation was increased, and the secretion of IgG λ antibody and the expression of the pro-inflammatory cytokine IL-6 were increased via NF-κB activation through PI3K/AKT and p38 signaling. SIGNOR-259868 0.466 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser491 GSCCTIMsPGEMEKH 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276360 0.368 SMURF1 protein Q9HCE7 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11278251 t miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  SIGNOR-272941 0.882 PLK3 protein Q9H4B4 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000452 11447225 t lperfetto Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3. SIGNOR-109239 0.706 sitaxentan chemical CHEBI:135736 ChEBI EDNRA protein P25101 UNIPROT down-regulates activity chemical inhibition -1 9171878 t miannu Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist.The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0. SIGNOR-258610 0.8 CDH4 protein P55283 UNIPROT CDH2 protein P19022 UNIPROT down-regulates quantity by repression 10090 BTO:0000165 18701479 f lperfetto Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts. SIGNOR-253107 0.513 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr565 KKKTEGTyDLPYWDR -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273945 0.35 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 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-252758 0.731 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 0.2 CDC42 protein P60953 UNIPROT WASL protein O00401 UNIPROT up-regulates activity binding 9606 10219243 t lperfetto In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules. SIGNOR-261868 0.919 SMARCB1 protein Q12824 UNIPROT SMARCA2 protein P51531 UNIPROT up-regulates activity binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65181 0.924 R2SP co-chaperone complex SIGNOR-C517 SIGNOR PPFIA2 protein O75334 UNIPROT up-regulates quantity by stabilization 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. Remarkably, R2SP is required for liprin-α2 expression and for the assembly of liprin-α2 complexes, indicating that R2SP functions in quaternary protein folding. SIGNOR-270942 0.2 BI 2536 chemical CID:11364421 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259702 0.8 ITGB1BP1 protein O14713 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257665 0.287 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1782 GAEIITQsPGRSSVA 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t gcesareni Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains SIGNOR-83100 0.36 Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 20176268 t scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. SIGNOR-268199 0.2 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 0.8 LARP1 protein Q6PKG0 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 BTO:0002181 28650797 t SARA LARP1-mTORC1 interaction occurs through direct protein-protein contacts. phosphorylated LARP1 facilitates mTORC1-dependent phosphorylation of S6K1 and 4EBP1 on the LARP1-containing mRNPs by scaffolding mTORC1. SIGNOR-260993 0.302 HTR2B protein P41595 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-257228 0.435 PAK1 protein Q13153 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation 9606 33432150 t miannu Pak1 phosphorylates NLRP3 and triggers inflammasome activation. SIGNOR-278967 0.2 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr252 HDGTVTHtFCGTIEY -1 9445476 t gcesareni The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k. SIGNOR-243338 0.727 DZIP3 protein Q86Y13 UNIPROT H2AC11 protein P0C0S8 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-271749 0.2 TBX21 protein Q9UL17 UNIPROT GATA3 protein P23771 UNIPROT down-regulates 9606 16386358 f Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both SIGNOR-254295 0.757 RUVBL2 protein Q9Y230 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-270854 0.698 PPM1F protein P49593 UNIPROT LATS1 protein O95835 UNIPROT down-regulates activity dephosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 30863499 t lperfetto POPX2 is capable of dephosphorylating LATS1 at Thr1079 (Figure xref ), which is a residue critical for LATS1 activity.|POPX2 might negatively regulate the activities of MST1 and LATS1 through dephosphorylation.|We found that POPX2 could dephosphorylate LATS1 on Threonine-1079, leading to inactivation of LATS1 kinase. SIGNOR-276989 0.2 tamsulosin chemical CHEBI:9398 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-258471 0.8 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 0.755 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 0.698 FFAR2 protein O15552 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-257075 0.307 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 0.8 CHMP4A protein Q9BY43 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-265529 0.706 MRPL20 protein Q9BYC9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262373 0.736 RAC1 protein P63000 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 27571105 t areggio Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK) SIGNOR-258972 0.404 SP1 protein P08047 UNIPROT PON1 protein P27169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 15380450 f miannu These data suggest that Sp1 acts as a positive regulator of PON1 transcription, and that an interaction between Sp1 and PKC is a key mechanism for the effect of Sp1 on PON1 transcription. SIGNOR-255212 0.268 TDGF1 protein P13385 UNIPROT NODAL protein Q96S42 UNIPROT up-regulates activity binding 9606 19874624 t Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. SIGNOR-251937 0.661 PRKN protein O60260 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272749 0.2 APOE protein P02649 UNIPROT MAPT protein P10636 UNIPROT up-regulates activity binding 7566652 t lperfetto Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3. SIGNOR-262588 0.567 FCN3 protein O75636 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 11907111 t lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP. SIGNOR-263410 0.672 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1616 NSHSPAGsAAISQQD 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275605 0.2 nafadotride chemical CHEBI:64191 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258854 0.8 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 0.257 SLC1A7 protein O00341 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-264806 0.8 GRIN1 protein Q05586 UNIPROT NMDA receptor_2C complex SIGNOR-C349 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-264124 0.612 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. SIGNOR-75788 0.601 HES1 protein Q14469 UNIPROT RCAN1 protein P53805 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000667 15866158 t Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism .... Chromatin immunoprecipitation (ChIP) analysis of keratinocytes overexpressing HES-1 showed that this protein can bind to the HES binding sites present in both distal and proximal promoters SIGNOR-252026 0.2 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 0.431 PTK2B protein Q14289 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates activity phosphorylation Tyr349 GNQFRANyFLQPELM 9606 21357692 t miannu Pyk2 Induces Tyrosine Phosphorylation of NPHP1 at Tyr-46, Tyr-349, and Tyr-721.|The expression of wild-type Pyk2 enhances the amount of co-precipitating PACS-1 with wild-type NPHP1 compared with the presence of the kinase-dead variant of Pyk2. SIGNOR-278271 0.461 EMSY protein Q7Z589 UNIPROT CBX1 protein P83916 UNIPROT up-regulates activity binding 9606 BTO:0000567 14651845 t miannu The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin. SIGNOR-263917 0.2 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Pro48 RSFLLRNpNDKYEPF -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263577 0.42 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 0.442 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000551;BTO:0000527 BTO:0000142 19478061 t miannu Transfection of wild-type ptprd resulted in the specific dephosphorylation of stat3 at tyrosine 705, a residue that must be phosphorylated for stat3 to be active SIGNOR-185933 0.517 CREB1 protein P16220 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by expression transcriptional regulation 10841026 t lperfetto Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription. SIGNOR-249619 0.633 PIK3R1 protein P27986 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-255300 0.936 FMR1 protein Q06787 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates quantity post transcriptional regulation 10090 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-262109 0.4 SRC protein P12931 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Tyr107 PHDPHKIyEFVNSGV 9606 35468896 t miannu Mechanistically, the progesterone-PGR axis activates SRC, which then mediates phosphorylation of IRF3 at Y107.|Taken together, these results suggest that P4 induces PGR-dependent activation of SRC, which promotes virus-triggered activation of IRF3 as well as induction of downstream antiviral genes.In the above experiments, we noticed that SeV-induced phosphorylation of IRF3S386 but not phosphorylation of TBK1S172 (p-TBK1S172, a hallmark for TBK1 activation) was increased by P4 treatment (Fig. 4g) or decreased by knockout of PGR (Fig. 4h). SIGNOR-279118 0.314 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr426 NEEWYVSyITRPEAE 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-42976 0.804 WDR62 protein O43379 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity relocalization 10090 30566428 t lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis SIGNOR-271716 0.294 CDK2 protein P24941 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 SIGNOR-C16 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-184160 0.2 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 0.849 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr381 EIEACQVyFTYDPYS -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251375 0.644 ELOVL3 protein Q9HB03 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267893 0.8 SRC protein P12931 UNIPROT KDR protein P35968 UNIPROT up-regulates activity phosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19050761 t miannu In contrast, our analysis showed that over-expression of c-Src significantly enhances the ability of VEGFR-2 to stimulate proliferation of PAE cells and over-expression of dominant negative Src (Src kinase-dead) inhibits the VEGFR-2 driven proliferation of PAE cells (XREF_FIG).|Taken together, the data demonstrate that Src kinases upon activation by VEGFR-2 phosphorylate Y1173 of VEGFR-2 (XREF_FIG). SIGNOR-279120 0.614 SRC protein P12931 UNIPROT PTK7 protein Q13308 UNIPROT up-regulates activity phosphorylation 9606 24703874 t miannu Because Ptk7 lacks intrinsic kinase activitiy, we suggest a positive feedback model in which pre-existing active Src phosphorylates PTK7 enabling it to interact with the SH2 domain of additional Src molecules to result in further activation. SIGNOR-279123 0.279 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252847 0.911 bexarotene chemical CHEBI:50859 ChEBI RXRG protein P48443 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259232 0.8 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 0.2 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267062 0.8 SESN3 protein P58005 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 t We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 SIGNOR-253561 0.437 PPP1CC protein P36873 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity dephosphorylation Ser8 MTTEQRRsLQAFQDY 9606 BTO:0000007 23499489 t lperfetto We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively  SIGNOR-264580 0.2 MAPK1 protein P28482 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-262524 0.383 STK4 protein Q13043 UNIPROT PDX1 protein P52945 UNIPROT down-regulates activity phosphorylation Thr11 EEQYYAAtQLYKDPC 9606 24633305 t miannu MST1 directly phosphorylated PDX1 at Thr11, resulting in its ubiquitination, degradation and impaired insulin secretion.|Thus, kinase activity is required for MST1 induced PDX1 degradation. SIGNOR-278303 0.2 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 0.357 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257962 0.8 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 0.364 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 0.637 TEAD proteinfamily SIGNOR-PF22 SIGNOR CNTF protein P26441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 31296870 t miannu In this model, treatment with LIF, but not IL-6, significantly elevated YAP/TAZ-TEAD transcriptional activity and sequentially increased expression of YAP1-targeted genes, CNTF and ANKRD at mRNA, in human PDAC cells SIGNOR-278034 0.2 MAPK1 protein P28482 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274076 0.287 MRPL24 protein Q96A35 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262369 0.722 ADRA1D protein P25100 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-257191 0.435 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-257606 0.7 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 0.319 vorinostat chemical CHEBI:45716 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-257916 0.8 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 0.615 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t 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-258119 0.8 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180784 0.2 RUNX3 protein Q13761 UNIPROT HSPD1 protein P10809 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255086 0.2 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 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-232208 0.798 IKBKB protein O14920 UNIPROT PFKFB3 protein Q16875 UNIPROT down-regulates activity phosphorylation Ser269 QGRIGGDsGLSSRGK -1 27585591 t miannu IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low. SIGNOR-277278 0.29 MET protein P08581 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Tyr1510 LVKLQQTyAALNSKA 9606 BTO:0000815 33087447 t miannu IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. SIGNOR-277532 0.272 MAPKAPK2 protein P49137 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-263080 0.477 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser268 LKSVRMLsGSKEKDR 9606 BTO:0000671 10908300 t gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. SIGNOR-79678 0.2 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 0.2 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity phosphorylation Ser320 GEGGRFFsPKEKDSP 12857729 t llicata Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa) SIGNOR-250742 0.439 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 0.8 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser372 PSPEPSMsPKMHRRR -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265962 0.515 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 0.2 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255030 0.853 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 0.511 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 0.2 PPP1CC protein P36873 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 23499489 t lperfetto Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation. SIGNOR-264579 0.247 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 0.755 tiotropium chemical CHEBI:90960 ChEBI CHRM2 protein P08172 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-258484 0.8 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER1 protein O15534 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-267970 0.717 TAF12 protein Q16514 UNIPROT ATF7 protein P17544 UNIPROT up-regulates activity binding 9534 BTO:0004055 15735663 t miannu We show that overexpression of hsTAF12 potentiates ATF7-induced transcriptional activation through direct interaction with ATF7, suggesting that TAF12 is a functional partner of ATF7. SIGNOR-225249 0.515 PTK2 protein Q05397 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 22952866 t miannu FAK directly phosphorylates cortactin at Y421 and Y466 and over-expression of cortactin Y421, Y466, and Y482 mutated to phenylalanine (3YF) prevented FAK-enhanced FA turnover and cell motility.|GFP-FAK re-expression in FAK-/- MEFs enhances FA turnover (XREF_FIG) and cortactin knockdown slows FA turnover (XREF_FIG). SIGNOR-278285 0.745 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 10090 17158101 t gcesareni Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis. SIGNOR-236867 0.805 NDUFS2 protein O75306 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262176 0.867 AHCYL2 protein Q96HN2 UNIPROT PAPOLA protein P51003 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268330 0.2 ITCH protein Q96J02 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates ubiquitination 9606 17028573 t gcesareni Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains. SIGNOR-150002 0.7 paclitaxel chemical CHEBI:45863 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 28298489 t miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. SIGNOR-259347 0.8 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 0.2 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 0.2 UCHL5 protein Q9Y5K5 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 16027725 t gcesareni Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases. SIGNOR-138879 0.662 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA3 protein P42263 UNIPROT up-regulates activity chemical activation 9606 30825796 t miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264610 0.8 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. 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-267333 0.8 CDK2 protein P24941 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 SIGNOR-C83 23028682 t llicata The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program. SIGNOR-199020 0.399 PTGES protein O14684 UNIPROT prostaglandin E2 smallmolecule CHEBI:15551 ChEBI up-regulates quantity chemical modification 9606 21983014 t The mPGES-1, one of three PGE2 synthases, is barely basally expressed, but is inducible by different stimuli and frequently co-expressed with COX-2. COX-2, mPGES-1 and PGE2 are enhanced during pain, inflammatory processes and in several cancer cells SIGNOR-254263 0.8 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 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-155377 0.332 HOXA9 protein P31269 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 17327400 t Luana Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its antiapoptotic and proproliferative effects in early cells.  SIGNOR-261632 0.2 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 0.523 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. SIGNOR-76100 0.304 CDK8 protein P49336 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-161561 0.566 SRC protein P12931 UNIPROT GRIK2 protein Q13002 UNIPROT up-regulates activity phosphorylation Tyr590 RFSPYEWyNPHPCNP 9606 BTO:0000007 25201974 t miannu GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. SIGNOR-276850 0.372 APC-c complex SIGNOR-C150 SIGNOR CDR2 protein Q01850 UNIPROT down-regulates quantity by destabilization ubiquitination 20383333 t lperfetto Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. SIGNOR-252024 0.2 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT2 protein P31751 UNIPROT down-regulates activity chemical inhibition 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-262011 0.8 romidepsin chemical CHEBI:61080 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-257990 0.8 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 10090 BTO:0000944 7518560 t lperfetto Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr. SIGNOR-235481 0.913 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163760 0.275 DDX1 protein Q92499 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260191 0.32 RAPGEF5 protein Q92565 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-183732 0.508 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 0.2 epinastine chemical CHEBI:51032 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-257779 0.8 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 7559487 t gcesareni To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%. SIGNOR-28884 0.28 ZNF217 protein O75362 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222118 0.553 TALDO1 protein P37837 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 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-267089 0.8 CENPT protein Q96BT3 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265204 0.728 romidepsin chemical CHEBI:61080 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-257996 0.8 MT-ND4 protein P03905 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262146 0.789 vitamin D smallmolecule CHEBI:27300 ChEBI calcidiol smallmolecule CHEBI:17933 ChEBI up-regulates quantity precursor of 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270567 0.8 GDNF protein P39905 UNIPROT DCX protein O43602 UNIPROT down-regulates quantity by repression 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. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. SIGNOR-252172 0.345 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 0.8 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 0.433 CDK5 protein Q00535 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 25730670 t miannu CDK5 activates DRP1 in BTICs.|To determine if CDK5 could directly phosphorylate DRP1, we performed an in vitro kinase assay with CDK5, its regulatory partner p25 and GST-DRP1 (wild type or S616A mutant) and found that CDK5 directly phosphorylates DRP1 on the S616 site (Fig. 7d). SIGNOR-278275 0.464 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 0.335 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 0.293 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 0.2 TELO2 protein Q9Y4R8 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 t miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. SIGNOR-272003 0.579 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr306 TTRLKEYtIKSHSSL 9606 15611134 t lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311 SIGNOR-132475 0.2 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 t Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201474 0.927 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 t lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-126871 0.274 SOX17 protein Q9H6I2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10549281 t gcesareni Two additional sox proteins, xsox17alfa and xsox3 , likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity SIGNOR-72006 0.686 BRSK1 protein Q8TDC3 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 9543386 t lperfetto Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo.Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-56473 0.483 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 0.243 AGO2 protein Q9UKV8 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 t lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. SIGNOR-140220 0.904 MAPK1 protein P28482 UNIPROT EPAS1 protein Q99814 UNIPROT up-regulates quantity by stabilization phosphorylation Ser484 SSCSTPNsPEDYYTS 9606 BTO:0006155 35191554 t miannu The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. SIGNOR-277585 0.25 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization binding 10090 12370803 t irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  SIGNOR-255810 0.451 SREBF1 protein P36956 UNIPROT MTTP protein P55157 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11111091 f miannu SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SIGNOR-252113 0.413 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260518 0.566 CCND1 protein P24385 UNIPROT MSI1 protein O43347 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20443831 f gcesareni We hypothesized that cyclin d1 may induce notch1 activity either by repressing numb or by inducing musashi 1 expression SIGNOR-165186 0.283 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser303 RVKEEPPsPPQSPRV 9606 8940068 t gcesareni Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. SIGNOR-44995 0.557 FZD4 protein Q9ULV1 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 t areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. SIGNOR-258967 0.704 MAPK1 protein P28482 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t miannu Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome SIGNOR-74712 0.605 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 0.7 MRPS27 protein Q92552 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-261446 0.698 E2F1 protein Q01094 UNIPROT NOX4 protein Q9NPH5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002195 18554521 f lperfetto Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F SIGNOR-254134 0.2 MDM2 protein Q00987 UNIPROT POLQ protein O75417 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22056306 t miannu In addition, we showed that Mdm2 is able to promote the PolH ubiquitination and degradation.|In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. SIGNOR-278827 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203592 0.777 RUNX1 protein Q01196 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002580 34902205 t lperfetto RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia. SIGNOR-272145 0.2 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 0.34 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-259174 0.2 IARS1 protein P41252 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-270354 0.2 FRZB protein Q92765 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, SIGNOR-51762 0.517 EEF1A1P5 protein Q5VTE0 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-269556 0.8 PRKCE protein Q02156 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-263048 0.2 GPR132 protein Q9UNW8 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-257396 0.407 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 0.45 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 0.592 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates quantity by destabilization ubiquitination Lys629 DSSPGFSkEIAAALA 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-271665 0.2 MAPKAPK5 protein Q8IW41 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser215 NSIRHNLsLHSRFMR 9606 21329882 t miannu Analysis of mutant alleles of FoxO3a showed that MK5 phosphorylated FoxO3a predominantly at S215, but that mutation of four of the identified sites was required to essentially abolish phosphorylation of FoxO3a by MK5 (\u201c4A\u201d) ( Figure\u00a04 C and data not shown).|MK5 phosphorylates and activates the transcription factor FoxO3a and potentially other FoxO factors. SIGNOR-279469 0.475 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. SIGNOR-181323 0.637 USF2 protein Q15853 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-254883 0.27 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 0.2 SMARCA4 protein P51532 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270738 0.869 BARD1 protein Q99728 UNIPROT BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR form complex binding 25400280 t lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. SIGNOR-263223 0.795 NFYB protein P25208 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 f miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. SIGNOR-255210 0.2 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 0.39 eprosartan chemical CHEBI:4814 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 1309870 t miannu The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SK&F 108566), was examined in a number of in vitro and in vivo assays. SIGNOR-258347 0.8 CDK1 protein P06493 UNIPROT CSNK2B protein P67870 UNIPROT up-regulates phosphorylation Ser209 QAASNFKsPVKTIR 9606 BTO:0000785 7578274 t lperfetto In cells, the casein kinase ii beta-subunit is phosphorylated at an autophosphorylation site and at a site (ser-209) that is maximally phosphorylated in mitotic cells. These studies provide strong biochemical evidence that p34cdc2 is the enzyme that phosphorylates ser-209 on the beta-subunit of ckii in mitotic cells. SIGNOR-29462 0.459 FHIT protein P49789 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis SIGNOR-143706 0.249 PIM3 protein Q86V86 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation -1 31730483 t miannu In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. ​(Fig.22c). SIGNOR-276773 0.246 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 0.7 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val58 KGVTVETvFSVDEFS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263583 0.298 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 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-181331 0.501 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 0.364 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 0.756 PTPN13 protein Q12923 UNIPROT TRIP6 protein Q15654 UNIPROT down-regulates activity dephosphorylation Tyr55 PLPSEQCyQAPGGPE 10090 BTO:0002572 17591779 t PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells. SIGNOR-248713 0.434 TBX5 protein Q99593 UNIPROT MTA2 protein O94776 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255256 0.2 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10734067 t gcesareni Here we show that the direct association between a p53 n-terminal peptide and mdm2 is disrupted by phosphorylation of the peptide on thr(18) but not by phosphorylation at other n-terminal sites, including ser(15) and ser(37). Thr(18) was phosphorylated in vitro by casein kinase (ck1). SIGNOR-75889 0.578 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 8131746 t gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf SIGNOR-36449 0.574 EGR2 protein P11161 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16054051 t fspada Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes SIGNOR-139292 0.534 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 0.7 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 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-256278 0.342 EPHA3 protein P29320 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Tyr153 TDKSAEDyNSSNALN 9606 26944939 t miannu Etk kinase directly phosphorylates and activates PAK1 in response to estrogen.|We demonstrated that estrogen-activated Etk directly phosphorylated PAK1 on Tyr153. SIGNOR-278398 0.277 NVP-BSK805 dihydrochloride chemical CID:57339395 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194934 0.8 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr886 GGEQDYDyLNDWGPR 9606 BTO:0000848 16371504 t lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. SIGNOR-143246 0.397 SLBP protein Q14493 UNIPROT H3Y2 protein P0DPK5 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-265416 0.2 TRIM27 protein P14373 UNIPROT WASHC1 protein A8K0Z3 UNIPROT up-regulates activity ubiquitination Lys220 DAPLSISkREQLEQQ 9606 23452853 t miannu Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport. SIGNOR-253514 0.2 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 0.293 PRL protein P01236 UNIPROT KRT5 protein P13647 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20103718 f Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. SIGNOR-251903 0.264 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169522 0.518 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr293 HRIDGKTyVIKRVKY 9606 BTO:0001282 16373505 t PKR autophosphorylates on Y101, Y162, and Y293. The introduction of the Y293F mutation causes significant defects in PKR autophosphorylation and eIF2α phosphorylation, providing evidence for a critical function of this phosphorylated residue. SIGNOR-251114 0.2 PTK2B protein Q14289 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates activity phosphorylation Tyr721 FDLSEQTyDFLGEMR 9606 21357692 t miannu Pyk2 Induces Tyrosine Phosphorylation of NPHP1 at Tyr-46, Tyr-349, and Tyr-721.|The expression of wild-type Pyk2 enhances the amount of co-precipitating PACS-1 with wild-type NPHP1 compared with the presence of the kinase-dead variant of Pyk2. SIGNOR-278273 0.461 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10346818 t amattioni Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation SIGNOR-67552 0.718 nalbuphine chemical CHEBI:7454 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258144 0.8 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 0.8 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 10649448 t gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression. SIGNOR-253061 0.315 FGD1 protein P98174 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260551 0.716 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 0.93 MCF2L protein O15068 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260560 0.751 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser270 EFRPRSKsQSSSNCS 9606 BTO:0000975;BTO:0001760;BTO:0000142 9312143 t lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. SIGNOR-51216 0.788 CHKA protein P35790 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 20708156 t miannu The data presented here provides evidence for a molecular mechanism by which CKI-dependent phosphorylation of Mdm2 at multiple sites triggers SCF \u03b2-TRCP -mediated Mdm2 destruction ( xref ). SIGNOR-279606 0.274 GABRG2 protein P18507 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263755 0.639 SND1 protein Q7KZF4 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity binding -1 12234934 t irozzo STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.]. SIGNOR-259134 0.479 PSMD3 protein O43242 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263353 0.896 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 0.25 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 0.619 SALL4 protein Q9UJQ4 UNIPROT ABCA3 protein Q99758 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21526180 f miannu we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples SIGNOR-255121 0.281 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser299 NQVTQRAsRRSDSAS 9606 17603046 t gcesareni Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved SIGNOR-156523 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA12 protein O60330 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-265698 0.2 SH3RF1 protein Q7Z6J0 UNIPROT HGS protein O14964 UNIPROT down-regulates quantity ubiquitination 9606 16084064 t miannu Importantly, ubiquitination of Hrs mediated by POSH caused the reduction of Hrs level via the ubiquitin-proteasome pathway. SIGNOR-278575 0.246 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191009 0.8 CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9600 BTO:0000567 26652733 t inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-270253 0.279 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG -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-274098 0.411 PDGFRB protein P09619 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 19275932 t miannu Here, we show that PDGFR-beta-phosphorylation of Abl kinases has functional consequences as PDGFR-beta phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases. SIGNOR-278318 0.527 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 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-36788 0.357 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 0.2 MPHOSPH10 protein O00566 UNIPROT RPS5 protein P46782 UNIPROT up-regulates activity binding -1 28813493 t miannu Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. SIGNOR-261175 0.626 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000482 24204001 f 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-254909 0.292 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity chemical activation 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate SIGNOR-264131 0.8 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates activity binding 9606 12782713 t gcesareni 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-252060 0.735 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 0.8 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 0.541 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase SIGNOR-76072 0.27 phosphatidylinositol 4-phosphate smallmolecule CHEBI:37530 ChEBI Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 22253445 f lperfetto Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. SIGNOR-260745 0.7 PPARG protein P37231 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity 9606 23128507 t PAX8-PPARγ fusion protein miannu The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway. SIGNOR-251997 0.456 RPS25 protein P62851 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-262426 0.909 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Thr403 HLPFVGFtYTSSCVL 9534 BTO:0000298 11283256 t miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). SIGNOR-275973 0.2 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr750 PAPDELVyQVPQSTQ -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273944 0.35 MZF1 protein P28698 UNIPROT CCN2 protein P29279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25899830 f miannu we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV. SIGNOR-226307 0.2 MAPK11 protein Q15759 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-119134 0.428 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 12181444 t gcesareni In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme. SIGNOR-91473 0.558 BHLHE41 protein Q9C0J9 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14672706 f lperfetto We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. SIGNOR-253714 0.533 CHFR protein Q96EP1 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 t miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. SIGNOR-271457 0.333 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-158324 0.756 FGF14 protein Q92915 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253441 0.2 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity destabilization 9606 BTO:0000567 16520378 t Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation. SIGNOR-266902 0.711 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu618 SEVKMDAeFRHDSGY -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261767 0.489 SNAI2 protein O43623 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255173 0.2 MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 t lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. SIGNOR-67143 0.848 BARD1 protein Q99728 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity ubiquitination 9606 25740706 t miannu As shown in xref , both FOXK2 and BARD1 enhanced the ubiquitination of ER\u03b1, with the extent of ubiquitination being enhanced when both FOXK2 and BARD1 were overexpressed.|These findings suggested that FOXK2 might act as a negative regulator of Estrogen receptor\u03b1, and its association with both Estrogen receptor\u03b1 and BRCA1/BARD1 could lead to the down-regulation of Estrogen receptor\u03b1 transcriptional activity, effectively regulating the function of Estrogen receptor\u03b1. SIGNOR-278803 0.427 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 0.389 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007 SIGNOR-C13 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-129935 0.886 HIRA complex 2 complex SIGNOR-C462 SIGNOR H3-3A protein P84243 UNIPROT up-regulates quantity by stabilization binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269440 0.2 MAPK15 protein Q8TD08 UNIPROT ELAVL1 protein Q15717 UNIPROT down-regulates activity phosphorylation 9606 26595526 t miannu ERK8 phosphorylates HuR to prevent its binding to PDCD4 mRNA A. ERK8 or control siRNA was transfected into HeLa cells for 48 h followed by treatment of cells with 0.5 mM H2O2 or PBS for 1 h. Cells were fixed and immunofluorescence was performed to monitor HuR localization. SIGNOR-278314 0.346 MECP2 protein P51608 UNIPROT SST protein P61278 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264676 0.297 HECW2 protein Q9P2P5 UNIPROT TP73 protein O15350 UNIPROT up-regulates quantity by stabilization ubiquitination 9534 BTO:0000298 12890487 t miannu P73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability. SIGNOR-269457 0.37 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 0.2 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 0.65 CAMK2D protein Q13557 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-275792 0.281 HDLBP protein Q00341 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 33941620 f miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. SIGNOR-266695 0.7 Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262511 0.2 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 0.763 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 0.8 UBE2I protein P63279 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11278694 t miannu  Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13. We also checked whether UBC9 is directly involved in pSTRA13 ubiquitination. Taken together, these results strongly suggest that pSTRA13 is targeted for proteolysis by the ubiquitin-dependent proteasome pathway through association with UBC9. SIGNOR-272579 0.326 ATM protein Q13315 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair. SIGNOR-151441 0.702 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 17157788 t miannu Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis. SIGNOR-151138 0.843 phenylalanine smallmolecule CHEBI:28044 ChEBI tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-264172 0.8 PRKCA protein P17252 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000017 15647376 t lperfetto Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc)  in the phosphorylation of ezrin t567. SIGNOR-133223 0.547 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 0.8 NLK protein Q9UBE8 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9534 BTO:0001538 20061393 t done miannu Here, we report that the transforming growth factor-beta-activated kinase (TAK1)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1. We show that NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain. The phosphorylation by TAK1-NLK pathway inhibits the transcriptional activity of FOXO1 and excludes FOXO1 from the nucleus, which is independent of phosphatidylinositol 3-kinase/Akt pathway.  SIGNOR-273907 0.613 SETD1B protein Q9UPS6 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546567 t miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. SIGNOR-265577 0.2 MAPK1 protein P28482 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol SIGNOR-137171 0.382 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT down-regulates phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t gcesareni Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation. SIGNOR-113960 0.402 PPARGC1A protein Q9UBK2 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255057 0.434 FLI1 protein Q01543 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-253921 0.312 RPS6KB1 protein P23443 UNIPROT TRIB2 protein Q92519 UNIPROT down-regulates quantity by destabilization phosphorylation Ser83 FRAVHLHsGEELVCK 9606 BTO:0002181 24089522 t miannu Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2. SIGNOR-275433 0.356 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation Thr539 INFFQDHtKLILCPL 9606 BTO:0000567 37596441 t miannu  Chk1 directly phosphorylates Plk1 to disturb its interaction with Sgo1.  SIGNOR-277914 0.314 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 t miannu Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion. SIGNOR-168382 0.2 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 0.454 ARHGAP1 protein Q07960 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260459 0.905 VPS4A protein Q9UN37 UNIPROT CHMP2A protein O43633 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-260846 0.911 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 0.2 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 8846784 t fstefani Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk. SIGNOR-44339 0.507 OGT protein O15294 UNIPROT PFKL protein P17858 UNIPROT down-regulates activity glycosylation Ser529 CVIPATIsNNVPGTD 9606 BTO:0000007 22923583 t lperfetto O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues SIGNOR-267585 0.277 AXL protein P30530 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 35022267 f miannu Gas6 and its main receptor AXL are overexpressed in pancreatic cancer and their expression correlates with poor prognosis.Gas6/AXL signalling in cancer cells is associated with tumour cell proliferation, epithelial mesenchymal transition and metastases. SIGNOR-277725 0.7 ANXA1 protein P04083 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 f miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups SIGNOR-261941 0.333 SVIP protein Q8NHG7 UNIPROT L3MBTL1 protein Q9Y468 UNIPROT down-regulates activity binding 9606 BTO:0000007 29018219 t lperfetto In response to DNA damage, VCP/p97, an ATPase which unfolds proteins, removes L3MBTL1 from H4K20me2, creating free H4K20me2 for 53BP1 to bind to (Fig. 3b). SIGNOR-262060 0.2 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Phe540 FSPMLGEfVSETESR -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain SIGNOR-263623 0.2 PPP2CA protein P67775 UNIPROT RBL1 protein P28749 UNIPROT up-regulates dephosphorylation 9606 15467457 t miannu Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation. SIGNOR-129749 0.623 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 0.737 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 0.587 PPP3CB protein P16298 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-248379 0.405 MAST2 protein Q6P0Q8 UNIPROT SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation 9606 16159897 t miannu Coexpression of MAST205 inhibits the activity of Na +/H+ exchanger NHE3.|Consistent with these results, we found that MAST205 phosphorylated NHE3 under in vitro conditions. SIGNOR-279229 0.456 AHSA1 protein O95433 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity binding 9606 BTO:0001519 16696853 t miannu The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells. SIGNOR-252213 0.297 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr271 CQLGQRIyQYIQSRF 9606 10910078 t lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site SIGNOR-79806 0.2 RPS4X protein P62701 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-262447 0.855 TFEB protein P19484 UNIPROT NEU1 protein Q99519 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276544 0.2 PAK4 protein O96013 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-263024 0.2 ALDH1A3 protein P47895 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265128 0.8 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI1 protein P08151 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni Gant58 is a gli antagonist that inhibits gli1-induced transcription SIGNOR-188863 0.8 WNT1 protein P04628 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway. SIGNOR-198846 0.692 SLC30A9 protein Q6PML9 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11782429 t lperfetto Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation. SIGNOR-113704 0.2 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 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-142218 0.743 GABA-A proteinfamily SIGNOR-PF61 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268610 0.2 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 0.78 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 0.91 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 0.271 RASGRF2 protein O14827 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-260574 0.498 MARK3 protein P27448 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 35017636 t miannu In addition, our results showed that MARK3 phosphorylated serine 323 of CDC25B, which is a phosphorylation site of another checkpoint kinase, MAPKAPK2, to induce cytoplasmic translocation of CDC25B .|In addition, our results showed that MARK3 phosphorylated serine 323 of CDC25B, which is a phosphorylation site of another checkpoint kinase, MAPKAPK2, to induce cytoplasmic translocation of CDC25B xref . SIGNOR-279223 0.26 lofepramine chemical CHEBI:47782 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258882 0.8 INS protein P01308 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates 9606 12242347 f gcesareni The specific interaction of active tc10 with cip4 2 suggested thatinsulinmight induce a change in the subcellular localization of cip4 2 SIGNOR-93062 0.266 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp572 PWHSFGAdSVPANTE -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261761 0.489 MAPK1 protein P28482 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser68 PSDLSPEsPMLSSPP -1 22577147 t lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta SIGNOR-264895 0.2 MARK3 protein P27448 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 35017636 t miannu In addition, our results showed that MARK3 phosphorylated serine 323 of CDC25B, which is a phosphorylation site of another checkpoint kinase, MAPKAPK2, to induce cytoplasmic translocation of CDC25B xref .|Indeed, MARK3 overexpression augmented the cytoplasmic localization, and reduced the nuclear localization, of CDC25B. SIGNOR-279224 0.26 ANKRD11 protein Q6UB99 UNIPROT CORO1B protein Q9BR76 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-266737 0.2 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 0.583 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 0.342 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 0.708 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 0.2 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 0.2 CSNK2A1 protein P68400 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000661 15818404 t lperfetto 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-244400 0.372 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser183 RARKMEDsKEKNGKK 9606 17540176 t miannu Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function SIGNOR-155349 0.289 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 10116 BTO:0003293 8276865 t milica LPA activates its own G protein-coupled receptor(s) leading to stimulation of phospholipase C and inhibition of adenylate cyclase. SIGNOR-37365 0.8 FADS6 protein Q8N9I5 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-267914 0.8 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 0.525 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT up-regulates activity cleavage Arg381 GMISLMKrPPGFSPF 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 t lperfetto Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1). SIGNOR-263547 0.779 CSNK2A1 protein P68400 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser186 EAGSGAAsSSGEDKE -1 12527891 t llicata Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. SIGNOR-250836 0.338 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 0.716 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 0.2 IKBKB protein O14920 UNIPROT TRIM23 protein P36406 UNIPROT down-regulates activity phosphorylation 9606 19716809 t miannu Phosphorylation of ARD1 by IKKbeta reduced its growth suppression effect. SIGNOR-279337 0.287 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 0.8 ADK protein P55263 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267840 0.8 TBL1X protein O60907 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000007 20181957 t miannu TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4). SIGNOR-271954 0.659 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization 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-269343 0.726 EGFR protein P00533 UNIPROT GPRC5A protein Q8NFJ5 UNIPROT down-regulates activity phosphorylation Tyr320 GDTLYAPySTHFQLQ 9606 25311788 t miannu EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells. SIGNOR-278334 0.387 MARK3 protein P27448 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates activity phosphorylation Ser406 TRLRRTEsVPSDINN 9606 22206009 t miannu C-TAK1 phosphorylates KSR1 at S392, forming a 14-3-3 binding site.|In mammalian cells, C-TAK1 has been shown to negatively regulate KSR1 by phosphorylation of Ser392. SIGNOR-279225 0.642 MAP3K14 protein Q99558 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17543278 t miannu Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues. SIGNOR-279340 0.26 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 0.2 MYO1C protein O00159 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-268820 0.329 GPC4 protein O75487 UNIPROT WNT3A protein P56704 UNIPROT up-regulates binding 9606 22302992 t gcesareni Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways SIGNOR-195749 0.35 KAT6A protein Q92794 UNIPROT CCL3 protein P10147 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12771199 t lperfetto We further demonstrate that the histone acetyltransferase, MOZ, can activate the MIP-1a promoter in T-cells and that this activation is largely dependent upon the proximal RUNX site. Moreover, we show that co-expression of MOZ and RUNX1 can activate the MIP-1a promoter. SIGNOR-251726 0.2 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr140 LRYLKYRtKTRASAT 9606 BTO:0000975 15107581 t Translocation from Endosome to Lysosome gcesareni As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2). SIGNOR-124348 0.282 ULK1 protein O75385 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates quantity by destabilization phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 25040165 t miannu ULK1 phosphorylates p62 at the Ser403 site. SIGNOR-278349 0.567 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 0.687 CFH protein P08603 UNIPROT C3 protein P01024 UNIPROT down-regulates activity binding 9606 19050261 t miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) SIGNOR-252141 0.918 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266459 0.8 ATF4 protein P18848 UNIPROT AARS1 protein P49588 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269414 0.2 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr973 RLGNGVLyASVNPEY -1 8940173 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-247193 0.582 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 0.628 LPAR3 protein Q9UBY5 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-257229 0.25 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 0.8 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 0.2 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 0.206 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 0.579 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 0.8 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 0.2 COL4A2 protein P08572 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-253243 0.49 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 0.849 PTPRS protein Q13332 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 12018405 t miannu Similarly, Pestana et al. (89) have reported that overexpression of RPTPsigma in human A431 carcinoma cells partially inhibits EGFR activation, whereas antisense mediated suppression of RPTPsigma expression enhances EGFR activation, substrate phosphorylation, and signalling.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types. SIGNOR-277145 0.43 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr534 SRTPSLPtPPTREPK 9606 17078951 t The effect has been demonstrated using P10636-8 lperfetto Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422 SIGNOR-150364 0.739 IRAK1 protein P51617 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates activity phosphorylation 9606 15767370 t miannu These data indicate that IRAK-1, but not IRAK-4, phosphorylates IRF7 in vitro. SIGNOR-278235 0.792 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser240 RLSSLRAsTSKSESS -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-250233 0.309 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser468 DLTIDSSsDEEEEEP 9606 19217413 t llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. SIGNOR-184047 0.332 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 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-268587 0.2 AMPK complex SIGNOR-C15 SIGNOR PRPS2 protein P11908 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 t 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-265732 0.241 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKVA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275870 0.2 CAMP protein P49913 UNIPROT FPR2 protein P25090 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11015447 t gcesareni Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1. SIGNOR-82701 0.533 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 0.953 olanzapine chemical CHEBI:7735 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258508 0.8 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT up-regulates activity cleavage Thr25 LLSGGVTtTPWSLAR 9606 BTO:0000089 26489954 t lperfetto The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb SIGNOR-263488 0.804 RNase H2 complex complex SIGNOR-C601 SIGNOR RNA_degradation phenotype SIGNOR-PH238 SIGNOR up-regulates 9606 21245041 f miannu RNA/DNA hybrids form during many key cellular processes including DNA replication (1), transcription (2) and telomere elongation (3). Ribonuclease H (RNase H) endonucleases degrade the RNA strand of such RNA/DNA hybrids and therefore have a central importance in cellular physiology. SIGNOR-280895 CSNK2A1 protein P68400 UNIPROT SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr61 ERRPESFtTPEGPKP 9606 phosphorylation:Thr62 RRPESFTtPEGPKPR 18490441 t lperfetto Phosphorylation of Thr61 is necessary for subsequent phosphorylation of Thr60 by CK2 in vitro. Inhibitors of CK2 also prevent degradation of SLBP at the end of S phase. Thus, phosphorylation of Thr61 by cyclin A/Cdk1 primes phosphorylation of Thr60 by CK2 and is responsible for initiating SLBP degradation. SIGNOR-265260 0.328 NR3C1 protein P04150 UNIPROT NFIL3 protein Q16649 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-268051 0.296 CEBPG protein P53567 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15322262 t lperfetto Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter. SIGNOR-268986 0.2 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 0.589 STK39 protein Q9UEW8 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Ser96 IEDLSQNsITGEHSQ -1 24043619 t miannu  We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function. SIGNOR-276597 0.569 GPR183 protein P32249 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256858 0.431 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 0.573 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr201 PHHVHPLtPLITYSN 9606 12556497 t llicata Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. SIGNOR-97819 0.772 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 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 12670876 t inferred from 70% family members 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-270088 0.2 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 0.497 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 0.435 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 t Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs. gcesareni Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators SIGNOR-175787 0.698 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 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-236416 0.76 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 0.2 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 0.791 PDGFB protein P01127 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity binding 9606 11331882 t miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta SIGNOR-107397 0.718 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 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-132927 0.62 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates activity dephosphorylation Tyr448 GDDSDEDyEKVPLPN 9606 16649996 t miannu Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling|adaptor protein 3BP2 serves as a binding protein and a physiological substrate of SHP-1. 3BP2 is phosphorylated on tyrosyl residue 448 in response to TCR activation, and the phosphorylation is required for T c SIGNOR-277172 0.57 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT up-regulates activity cleavage Asn66 GCPKESCnLFVLKDT -1 14583471 t miannu Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr. SIGNOR-256346 0.375 FYN protein P06241 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir. SIGNOR-78702 0.38 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 0.284 PHACTR1 protein Q9C0D0 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates activity binding 9606 BTO:0001949 21939755 t miannu Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process. SIGNOR-260062 0.537 ITGB4 protein P16144 UNIPROT A6/b4 integrin complex SIGNOR-C174 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-253200 0.77 BCOR protein Q6W2J9 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity binding 9606 BTO:0000007 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-252238 0.55 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr654 DIHHIDYyKKTTNGR 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses. SIGNOR-236199 0.2 CDON protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t lperfetto In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. SIGNOR-150282 0.498 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 0.78 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser325 PGAPPPAsKPKLWSL -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-263061 0.2 AKT3 protein Q9Y243 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-61565 0.518 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 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-176292 0.8 OPHN1 protein O60890 UNIPROT RHOA protein P61586 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-268397 0.636 N-tert-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide chemical CHEBI:104131 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258896 0.8 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249361 0.681 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr486 SRRIAVEySDSDDDS 9606 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-259077 0.582 miR-495 mirna URS000075C517_9606 RNAcentral Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 19219026 t Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  SIGNOR-268044 0.4 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9606 22182578 t Luana  Salbutamol is a well-known β2 adrenoceptor (β2AR) partial agonist. | In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human β2AR (hβ2AR). The transfected hβ2AR showed similar affinity for BCSDs and salbutamol SIGNOR-258326 0.8 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 0.881 MTERF4-NSUN4 mitochondiral ribosomal assembly complex complex SIGNOR-C602 SIGNOR Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000887 15701510 t miannu The nicotinic ACh receptor is a member of the pentameric “Cys-loop” superfamily of transmitter-gated ion channels, which includes neuronal ACh receptors, GABAA receptors, 5-HT3 receptors and glycine receptors.1, 2, 3, 4, 5 The channel is found in high concentrations at the nerve–muscle synapse, where it mediates fast chemical transmission of electrical signals in response to ACh released from the nerve terminal into the synaptic cleft. It is a large (290 kDa) glyco-protein, assembled from a ring of homologous subunits (α, γ, α, β, δ) and divided into three domains SIGNOR-280902 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 0.648 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 0.504 STAT5A protein P42229 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15840840 t lperfetto PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers.|PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLRL or GHR. SIGNOR-268990 0.2 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1249 HGHVSDAsISLGEPV -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-262906 0.701 EIF2B2 protein P49770 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269135 0.696 PRKACA protein P17612 UNIPROT PHOX2A protein O14813 UNIPROT down-regulates phosphorylation Ser153 RKQERAAsAKGAAGA 9606 19564421 t llicata Phox2a becomes phosphorylated by protein kinase a (pka) on ser153, which prevents association of phox2a with dna and terminates p27(kip1) transcription. SIGNOR-186462 0.307 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 0.7 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr291 DDQRSMGyDDLDYGM -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-246496 0.922 LIN7C protein Q9NUP9 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-203491 0.649 MAP3K9 protein P80192 UNIPROT MAP3K9 protein P80192 UNIPROT up-regulates activity phosphorylation Thr312 TKMSAAGtYAWMAPE 10029 15610029 t lperfetto We present here biochemical and biophysical evidence that MLK1 is activated by autophosphorylation in (or near) the activation loop. The activation loops of the MLK family are highly homologous, and so one might predict that the same residues would be key to their activation. Functional data presented here, however, demonstrate that the key residue for activation of MLK1, Thr312, differs from the key residue for activation of MLK3. SIGNOR-249388 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR MYOM1 protein P52179 UNIPROT down-regulates activity phosphorylation Ser618 ARLKSRPsAPWTGQI -1 9029142 t miannu This interaction is regulated by phosphorylation of Ser482 in the linker between myomesin domains My4 and My5. Myomesin phosphorylation at this site by cAMP-dependent kinase and similar or identical activities in muscle extracts block the association with titin. SIGNOR-263156 0.2 ATF6 protein P18850 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14973138 t Luana  Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β.  SIGNOR-261565 0.821 CCT3 protein P49368 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-272864 0.754 CLASP2 protein O75122 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity binding 9534 BTO:0004055 19638411 t lperfetto IQGAP1 is a novel CLASP2-interacting protein| nonphosphorylated CLASP2 on microtubules is allowed to associate with IQGAP1 for the coupling of microtubules to actin filaments at the front of migrating cells. SIGNOR-264828 0.416 CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000876 BTO:0001103 19436055 f apalma As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-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-255586 0.2 GARS1 protein P41250 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270480 0.8 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 0.484 IL1B protein P01584 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 BTO:0002417 32454942 f miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS SIGNOR-263820 0.588 SGK3 protein Q96BR1 UNIPROT PTOV1 protein Q86YD1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 VRAVRSRsWPASPRG 9606 34654719 t miannu In this study, we find that the understudied serum and glucocorticoid-induced kinase-2 (SGK2) phosphorylates PTOV1 at S36. SIGNOR-279283 0.2 SLK protein Q9H2G2 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation 9606 19640899 t miannu The Ste20 like kinase SLK promotes p53 transactivation and apoptosis.|Thus SLK induces p53 phosphorylation and transactivation, which enhances apoptosis after in vitro ischemia-reperfusion injury. SIGNOR-279285 0.256 PRKCE protein Q02156 UNIPROT NSF protein P46459 UNIPROT up-regulates activity phosphorylation Thr461 NRHIKAStKVEVDME 9606 20962217 t miannu PKCepsilon phosphorylation enhances the ATPase activity of NSF.|These results indicate that PKC\u03b5 phosphorylates NSF at both S460 and T461 in vitro . SIGNOR-278299 0.234 RPS6KA3 protein P51812 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Ser46 TASTGNLsSSFMEEI 9606 29563609 t miannu These results demonstrate that TRAF6 K63 ubiquitination might be regulated by an RSK2 mediated phosphorylation dependent mechanism and phosphorylation of TRAF6 at Ser46, 47 and 48 enhances its ubiquitin mediated inflammation signaling. SIGNOR-278302 0.272 GABRB1 protein P18505 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-263754 0.621 MSX1 protein P28360 UNIPROT DLX2 protein Q07687 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-240929 0.399 FGF12 protein P61328 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253428 0.309 RPLP0 protein P05388 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262451 0.828 CSF1R protein P07333 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24890514 f miannu CSF-1R also induces the expression/activation of several other regulators of multipotent progenitor proliferation/differentiation (Fig. 4A). These include [‚Ķ] the adaptor proteins suppressor of cytokine signaling 1 (Socs1) SIGNOR-255574 0.489 AKT1 protein P31749 UNIPROT CABLES1 protein Q8TDN4 UNIPROT down-regulates activity phosphorylation Thr415 AFGARRNtIDSTSSF -1 25361894 t miannu Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. SIGNOR-276757 0.34 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 0.319 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 0.7 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 0.257 GRK2 protein P25098 UNIPROT ADIPOR1 protein Q96A54 UNIPROT down-regulates quantity by destabilization phosphorylation Ser205 EKVSRTFsKLDYSGI 10090 BTO:0003324 35611695 t miannu . GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. SIGNOR-277594 0.2 WDR5 protein P61964 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-264480 0.918 PRKAA1 protein Q13131 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 t 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-265731 0.2 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264441 0.328 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264730 0.435 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 0.8 GNAS protein P63092 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 t gcesareni Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7. SIGNOR-191561 0.294 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 0.661 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 0.325 VPS18 protein Q9P253 UNIPROT PLK2 protein Q9NYY3 UNIPROT down-regulates quantity by destabilization ubiquitination 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-271550 0.2 TNF protein P01375 UNIPROT TNFRSF21 protein O75509 UNIPROT up-regulates binding 9606 BTO:0000142 9714541 t gcesareni We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain. SIGNOR-59745 0.337 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT down-regulates activity phosphorylation Ser37 TASEHRKsSKPIMEK -1 9389649 t lperfetto Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. SIGNOR-248992 0.329 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr76 LRASRLGtTRTPSSY 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-249031 0.316 NLGN2 protein Q8NFZ4 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-264151 0.825 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Thr236 NIACVILtFKEPFGT 9606 BTO:0001260 20649491 t lperfetto A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity. SIGNOR-167053 0.2 PLK1 protein P53350 UNIPROT MAD2L1BP protein Q15013 UNIPROT down-regulates activity phosphorylation Ser102 KHFYRKPsPQAEEML 9606 BTO:0000567 31118282 t miannu Purified Plk1 bound to p31comet and phosphorylated it, resulting in the suppression of its activity (with TRIP13) to disassemble checkpoint complexes. We conclude that Plk1 phosphorylates p31 on S102 and on five additional sites. The phosphorylation of the additional sites was possibly not detectable in HeLa cell extracts due to the opposing action of protein phosphatases. SIGNOR-265970 0.41 POLR2J3 protein Q9H1A7 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-266173 0.691 FER protein P16591 UNIPROT FER protein P16591 UNIPROT up-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ -1 19159681 t miannu  Mutation analysis unveiled a tyrosine (Tyr(616)) embedded in the Hsp90 recognition loop, which is required for the kinase activity of Fer. Replacement of this tyrosine by phenylalanine (Y616F) disabled the auto-phosphorylation activity of Fer and abolished its ability to phosphorylate Stat3.  SIGNOR-276236 0.2 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser415 HKLDVSRsPPLMVKK 9606 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS‚‚PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573‚‚577 (see Supplementary Information, Table S2). SIGNOR-249307 0.433 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 9047237 t lperfetto Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient. SIGNOR-46859 0.804 AMPK complex SIGNOR-C15 SIGNOR ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 12015362 t lperfetto 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-216655 0.559 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 25728771 t inferred from 70% family members lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-270092 0.2 JAG2 protein Q9Y219 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-82401 0.625 ARNT protein P27540 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 14764593 t lperfetto The functional transcription factor exists as a heterodimeric complex consisting of HIF-1alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction. SIGNOR-253720 0.787 TRAF6 protein Q9Y4K3 UNIPROT ECSIT protein Q9BQ95 UNIPROT down-regulates activity ubiquitination 10090 21525932 t Giorgia Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation SIGNOR-260370 0.79 ALDH9A1 protein P49189 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269694 0.8 PPM1E protein Q8WY54 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 11864573 t The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. SIGNOR-248760 0.303 CHEK1 protein O14757 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation Ser273 SMLNKNPsLRPSAIE 9606 19734889 t lperfetto We demonstrate that chk1 (checkpoint kinase 1) directly activates nek11 by phosphorylating it on ser 273 SIGNOR-187863 0.264 AR protein P10275 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression binding 9606 9162033 t lperfetto Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity SIGNOR-48513 0.547 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 0.424 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 0.654 CDK2 protein P24941 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation Ser163 KSQKLLRsPRKPTRK 12560341 t llicata  A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.  SIGNOR-250733 0.745 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Thr577 AENGLLMtPCYTANF 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-248323 0.361 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161634 0.383 TNK2 protein Q07912 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr269 QLRGDCMyAPLLGVP 9606 20383201 t miannu Ack1 interacted with and phosphorylated AR protein at Tyr 267 and Ack1 was shown to be required for optimal AR target gene expression and AR recruitment.|Two intracellular tyrosine kinases, Ack1 (activated cdc42 associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. SIGNOR-278194 0.545 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser376 PPAPAYLsSPLALPS 9606 SIGNOR-C14 SIGNOR-C14 12657630 t IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376. SIGNOR-251286 0.962 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 9606 17623675 t lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. SIGNOR-156895 0.466 ROCK1 protein Q13464 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser72 SSAVRLRsSVPGVRL 9534 BTO:0000298 9565595 t lperfetto We found that vimentin, the most widely expressed intermediate filament protein, served as an excellent substrate for Rho-associated kinase (Rho-kinase) and that vimentin phosphorylated by Rho-kinase lost its ability to form filaments in vitro. Two amino-terminal sites on vimentin, Ser38 and Ser71, were identified as the major phosphorylation sites for Rho-kinase, and Ser71 was the most favored and unique phosphorylation site for Rho-kinase in vitro.  SIGNOR-248998 0.367 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16243 0.577 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 0.344 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 0.2 BST1 protein Q10588 UNIPROT NADP(+) smallmolecule CHEBI:18009 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264251 0.8 SYK protein P43405 UNIPROT LRRFIP1 protein Q32MZ4 UNIPROT up-regulates activity phosphorylation 9606 19151749 t miannu However, this inhibitory activity TRIP can be reversed by the co-expression of Syk, which might inhibit the activity of cytoplasmic TRIP, sequester TRIP from important nucleolar targets or even counter TRIP 's inhibitory effects on TRAF and TNF signaling by regulating the activity of alternative components of the pathway.|Syk induces phosphorylation of TRIP on tyrosine. SIGNOR-279297 0.2 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 0.296 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 0.395 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 0.747 p38 proteinfamily SIGNOR-PF16 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 t inferred from 70% family members gcesareni We show that prak activates p53 by direct phosphorylation. SIGNOR-270126 0.2 ACE2 protein Q9BYF1 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 f doi.org/10.1101/2020.03.09.983247 miannu Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell–cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity. SIGNOR-260286 0.7 NRL protein P54845 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253818 0.373 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000552 14744793 t gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-248070 0.653 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 t llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. SIGNOR-182757 0.393 CSNK2A1 protein P68400 UNIPROT GPI protein P06744 UNIPROT down-regulates activity phosphorylation Ser185 GPRVWYVsNIDGTHI 9606 BTO:0000459 15637053 t llicata It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity.  SIGNOR-250869 0.333 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 0.2 PDK2 protein Q15119 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a €œgain control€ for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity SIGNOR-249630 0.749 imatinib chemical CHEBI:45783 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193375 0.8 paracetamol chemical CHEBI:46195 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000876 17884974 t Luana Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man SIGNOR-257757 0.8 ENO3 protein P13929 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-266530 0.8 TNKS protein O95271 UNIPROT RNF146 protein Q9NTX7 UNIPROT up-regulates activity 9606 BTO:0000007 21478859 f 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-263338 0.723 TRIM13 protein O60858 UNIPROT CD3D protein P04234 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17314412 t miannu RFP2, a gene frequently lost in various malignancies, encodes a protein with RING finger, B-box, and coiled-coil domains that belongs to the RBCC/TRIM family of proteins.Rfp2 Regulates the Stability of the ERAD Substrate CD3-δ. In summary, these experiments demonstrate that Rfp2 functions as a RING-dependent ERAD E3 ubiquitin ligase and regulates the degradation of the ER substrate, CD3-δ. SIGNOR-271644 0.2 CBX1 protein P83916 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-266754 0.359 SPAG5 protein Q96R06 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-271719 0.465 SRC protein P12931 UNIPROT SPRY2 protein O43597 UNIPROT up-regulates phosphorylation Tyr55 AIRNTNEyTEGPTVV 9606 15564375 t lperfetto Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway. SIGNOR-131189 0.565 CAMKK2 protein Q96RR4 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 15980064 t lperfetto 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-217496 0.602 Linsitinib chemical CID:11640390 PUBCHEM IGF1R protein P08069 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-262028 0.8 RPS6KA2 protein Q15349 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-248949 0.515 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260142 0.7 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 0.617 ATM protein Q13315 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser162 TCSENGVsLCLPRLE 9606 23435430 t miannu Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. SIGNOR-276488 0.264 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL2 protein P10415 UNIPROT up-regulates phosphorylation 9606 10669763 t inferred from 70% family members gcesareni Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association. SIGNOR-270064 0.2 COX5B protein P10606 UNIPROT Cytochrome c oxidase-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-267749 0.794 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 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-116476 0.756 bethanechol chemical CHEBI:3084 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-258622 0.8 lisuride chemical CHEBI:51164 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258886 0.8 RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR Meiotic_recombination phenotype SIGNOR-PH162 SIGNOR up-regulates 10090 BTO:0000534 21242291 f 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-264539 0.7 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser422 RFHSLPFsLTKMPNT 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-204720 0.548 PPME1 protein Q9Y570 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity demethylation 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 |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. SIGNOR-265748 0.905 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000149 1706616 t gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. SIGNOR-21203 0.2 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 0.2 TP53 protein P04637 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267465 0.335 PRKRA protein O75569 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 t lperfetto Immunoprecipitation and reconstitution experiments in various systems have shown that Dicer associates with proteins in the Argonaute (Ago) family of endonucleases and with specific double-stranded RNA-binding proteins (dsRBPs) (3–7). | In humans, these dsRBPs are protein activator of PKR (PACT) (5) and trans-activation response RNA-binding protein (TRBP) (3,4). SIGNOR-255318 0.769 GABRA3 protein P34903 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263756 0.605 ULK3 protein Q6PHR2 UNIPROT CHMP4C protein Q96CF2 UNIPROT down-regulates activity phosphorylation 9606 26011858 t miannuccelli CHMP4C was phosphorylated by recombinant ULK3 in these experiments, whereas CHMP4A and CHMP4B were not (Figure 7\u2014figure supplement 1A). SIGNOR-279771 0.286 Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 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-270936 0.7 BLK protein P51451 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268217 0.648 MAPK12/CARM1 complex SIGNOR-C218 SIGNOR SNTB1 protein Q13884 UNIPROT up-regulates activity binding 29681515 t apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255978 0.368 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 0.511 FANCM protein Q8IYD8 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-263248 0.936 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 0.373 APC-c complex SIGNOR-C150 SIGNOR ANLN protein Q9NQW6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16040610 t miannu  Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin. SIGNOR-272655 0.263 ENO2 protein P09104 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-266529 0.8 PAK proteinfamily SIGNOR-PF13 SIGNOR NF2 protein P35240 UNIPROT down-regulates phosphorylation 9606 18071304 t inferred from 70% family members lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, SIGNOR-269976 0.2 LATS2 protein Q9NRM7 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-218038 0.821 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 0.477 PP2B proteinfamily SIGNOR-PF18 SIGNOR JUN protein P05412 UNIPROT up-regulates dephosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000938;BTO:0000017 17215518 t lperfetto Importantly, pp2b not only dephosphorylates the c-jun at ser-243 but also interacts with c-jun in pma-treated cells. Pma stimulates the association of the pp2b/c-jun/sp1 complex with the promoter. These findings indicate the dephosphorylation of c-jun c terminus is required for the c-jun/sp1 interaction SIGNOR-152006 0.2 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 0.8 RORA protein P35398 UNIPROT SHH protein Q15465 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-266846 0.251 HDAC1 protein Q13547 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 17183360 t lperfetto Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1. SIGNOR-217409 0.542 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 0.25 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 t lperfetto Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported SIGNOR-167552 0.296 PRKCB protein P05771 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 t miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. SIGNOR-276460 0.2 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 0.819 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 0.749 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 0.397 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 0.722 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 9204908 t miannu MTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. SIGNOR-250292 0.926 SLBP protein Q14493 UNIPROT H2BU1 protein Q8N257 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-265388 0.2 TRIP11 protein Q15643 UNIPROT THRB protein P10828 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-50421 0.314 SF3B2 protein Q13435 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268404 0.924 SRSF11 protein Q05519 UNIPROT LRP8 protein Q14114 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 10090 31269452 t miannu We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. SIGNOR-269670 0.2 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr405 STSSSIIySSQEDVK 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-169703 0.716 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 0.2 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 29955047 t lperfetto Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.|Use of a TC-PTP substrate trapping mutant for immunoprecipitation analysis showed that TC-PTP dephosphorylates four different tyrosine residues of Flk-1 -- Y1052, Y1057, Y1212, and Y994 -- in human umbilical vein endothelial cells; however, it did not dephosphorylate the Y1173 residue of Flk-1 38. SIGNOR-276962 0.566 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 0.351 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI AR protein P10275 UNIPROT up-regulates chemical activation 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251533 0.8 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser89 KQKQPSFsAKKMTEK 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276380 0.295 NDUFV1 protein P49821 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262183 0.863 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 0.492 ponatinib chemical CHEBI:78543 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001669 23539538 t miannu Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells SIGNOR-259272 0.8 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser325 LTSVSRGsSLKILSK 9606 10521508 t Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. SIGNOR-260899 0.2 CDK2 protein P24941 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity phosphorylation Thr416 EANSRCQtPIKMKPN 9606 BTO:0000007 23241245 t Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1. SIGNOR-255656 0.547 PTPRB protein P23467 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well SIGNOR-269931 0.432 POLR1H protein Q9P1U0 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16373708 f miannu ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. SIGNOR-259908 0.2 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 10212258 t Manara Tyrosine Phosphorylation of Rad51 by ABL1 Enhances the Interaction between Rad51 and Rad52 | our studies of Rad51·Rad52 complex formation in vitro and in vivo suggest that the ATM and ABL1-mediated signaling is likely to promote repair given the biochemical evidence that Rad51 acts in concert with Rad52 in homologous recombination SIGNOR-260777 0.773 TLR4 protein O00206 UNIPROT TLR4 protein O00206 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-252066 0.2 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 9716487 t lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238634 0.639 PPP3CA protein Q08209 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-248681 0.629 PRKCQ protein Q04759 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates activity phosphorylation Ser591 DKEKSKGsLKRK 9606 BTO:0000914 35258455 t miannu SHP-1 phosphorylation is mediated through PKC-θ. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 'folded' state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in vivo. SIGNOR-277590 0.2 MAPK9 protein P45984 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation 9606 25377781 t miannu Activation of c-Src by JNK2 was accompanied by the phosphorylation of c-Src on threonine residue (s).|JNK2 directly phosphorylates c-Src and activates its auto phosphorylation. SIGNOR-279221 0.355 albuterol sulfate chemical CHEBI:2550 ChEBI ADRB2 protein P07550 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-206682 0.8 SCN4A protein P35499 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253405 0.8 EPO protein P01588 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-251783 0.349 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 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-248514 0.408 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 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-268585 0.2 PTK6 protein Q13882 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Tyr64 VDTSQVLyEWEQGFS 9606 20026641 t miannu PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo. SIGNOR-278288 0.305 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16874298 t lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo SIGNOR-148323 0.619 PHF2 protein O75151 UNIPROT H3-3A protein P84243 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-264519 0.2 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 0.7 GRIP1 protein Q9Y3R0 UNIPROT KIF5C protein O60282 UNIPROT up-regulates activity binding 9606 BTO:0000142 31757889 t miannu HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro SIGNOR-264061 0.324 PPP2R1A protein P30153 UNIPROT PPP2CA protein P67775 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-138883 0.959 GIT1 protein Q9Y2X7 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 14523024 t gcesareni Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation SIGNOR-118454 0.557 TP63 protein Q9H3D4 UNIPROT SYNE3 protein Q6ZMZ3 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-263280 0.2 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 0.301 PINK1 protein Q9BXM7 UNIPROT UBA52 protein P62987 UNIPROT up-regulates phosphorylation Ser65 DYNIQKEsTLHLVLR 10090 BTO:0002572 24784582 t Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. SIGNOR-270342 0.385 SMARCA4 protein P51532 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270726 0.758 FYN protein P06241 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation 9606 14707117 t miannu As shown in XREF_FIG F, Fyn immunoprecipitates from activated T cells induced the tyrosine phosphorylation of WASp, but neither WASpDeltaPro nor WASpY291F mutant proteins were phosphorylated in this assay. SIGNOR-279333 0.561 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 0.259 DHODH protein Q02127 UNIPROT ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267432 0.8 PTK6 protein Q13882 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Tyr333 NIMRTYTyEKLLWTT 9606 20026641 t miannu PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo. SIGNOR-278289 0.305 PLK1 protein P53350 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates activity phosphorylation 9606 30456393 t miannu Phosphorylation of NuMA by Plk1 at 1833/34 residue can impact its cortical localization.|These data strongly suggest that Plk1 negatively regulate cortical NuMA localization and that this impact of Plk1 on NuMA is presumably independent of LGN, at least in the anaphase cells. SIGNOR-279345 0.534 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73898 0.699 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 0.359 CDKN2C protein P42773 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44601 0.88 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 0.515 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 22153608 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-195221 0.449 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 0.386 paclitaxel chemical CHEBI:45863 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 28298489 t miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. SIGNOR-259346 0.8 DNMT1 protein P26358 UNIPROT MBD2 protein Q9UBB5 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 15618232 f lperfetto We then examined the levels of DNMT1 and methylated DNA-binding protein 2 (MBD2) expressions in these cells to determine whether this reduction in uPA expression is associated with changes in the DNA methylation machinery. Our results showed that ectopic expression of RAS induced DNMT1 expression and activity and inhibited MBD2 expression. SIGNOR-254128 0.705 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 0.253 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 0.466 ERBB2 protein P04626 UNIPROT FASN protein P49327 UNIPROT up-regulates activity phosphorylation 9606 27692180 t miannu Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression ( xref ; xref ).|Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression. SIGNOR-278399 0.442 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 0.368 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 0.2 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 0.2 quetiapine chemical CHEBI:8707 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 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-258532 0.8 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000975 11498022 t gcesareni Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor. The aps adapter protein couples theinsulinreceptor to the phosphorylation of c-cbl and facilitates ligand-stimulated ubiquitination of theinsulinreceptor. SIGNOR-109691 0.647 SMAD7 protein O15105 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-112645 0.58 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 0.435 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 0.398 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 0.461 HBB protein P68871 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000876 11901318 f Regulation of expression miannu Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes. SIGNOR-251752 0.3 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser76 SNLQRMGsSESTDSG 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163150 0.857 CDK1 protein P06493 UNIPROT KRT18 protein P05783 UNIPROT up-regulates phosphorylation Ser34 RPVSSAAsVYAGAGG 9606 9524113 t lperfetto We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins SIGNOR-55994 0.338 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257924 0.8 HTR1D protein P28221 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256721 0.435 mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 f lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. SIGNOR-268322 0.7 CD3 complex SIGNOR-C432 SIGNOR ZAP70 protein P43403 UNIPROT up-regulates activity binding 9534 1423621 t We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction. SIGNOR-252304 0.696 FGFR3 protein P22607 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 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-251139 0.631 EPHA3 protein P29320 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr535 MDSYSGPyGDMRLET 9606 20570899 t miannu Src and Etk share some common substrates due to the high degree of homology of their kinase domains, thus we examined whether the increased Etk expression could also contribute to AR Y534 phosphorylation.|This is supported by our observations that the association between Etk and AR is increased after castration and Etk induces tyrosine phosphorylation of AR, leading an increase in AR stability and transcriptional activity under androgen depleted conditions. SIGNOR-279370 0.273 PRKCA protein P17252 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress SIGNOR-91826 0.536 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19860666 t 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-188884 0.709 EGR1 protein P18146 UNIPROT PITX1 protein P78337 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-254916 0.514 HSPA1A protein P0DMV8 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-252416 0.256 RPS6KA5 protein O75582 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser7 sSAEGAAK 12213813 t lperfetto HMGN1 (formerly known as HMG-14) phosphorylation at Ser6 occurs concomitantly with IE gene expression. | MSK2 seems to be the most important kinase responsible for this modification |Accordingly, it was suggested that HMGN1 phosphorylation reduces binding of the protein to the nucleosomes SIGNOR-262988 0.62 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 0.723 UBE3A protein Q05086 UNIPROT TSC2 protein P49815 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18298802 t miannu  An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase. SIGNOR-271396 0.629 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265907 0.8 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 0.678 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 0.455 DVL1 protein O14640 UNIPROT RND1 protein Q92730 UNIPROT up-regulates 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199387 0.273 ITGB2 protein P05107 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257711 0.559 SNAI1 protein O95863 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-255156 0.758 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 0.364 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 0.396 AAAS protein Q9NRG9 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-262067 0.542 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 0.257 PTGFR protein P43088 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256810 0.373 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III SIGNOR-248926 0.676 MACF1 protein Q9UPN3 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization 9606 16815997 f gcesareni 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-147448 0.404 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201534 0.96 MTOR protein P42345 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-262534 0.73 CREB1 protein P16220 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000157 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-253797 0.296 UBR1 protein Q8IWV7 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells SIGNOR-128169 0.492 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 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-249407 0.68 SGK1 protein O00141 UNIPROT APBB1 protein O00213 UNIPROT down-regulates activity phosphorylation Ser610 ECRVRFLsFLAVGRD 9606 26188042 t miannu In the present study, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 attenuates the interaction between FE65 and APP (XREF_FIG).|In this regard, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 abolishes the effect of FE65 on APP processing and the amount of secreted Abeta is comparable to APP + Mock control (XREF_FIG). SIGNOR-278220 0.345 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 0.356 MAPK1 protein P28482 UNIPROT PBK protein Q96KB5 UNIPROT up-regulates activity phosphorylation 9606 35546143 t miannuccelli In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2.|TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC. SIGNOR-279744 0.283 CCKAR protein P32238 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257035 0.252 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR SUDS3 protein Q9H7L9 UNIPROT up-regulates activity phosphorylation Ser228 RTLNKLKsPKRPASP 9606 BTO:0000007 15489224 t miannu Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription. the dimerization of the phosphorylation-deficient mutant of mSds3 (S228A) was not greatly enhanced by p35 when compared with wild type (Fig. 5D). This finding suggests that the phosphorylation of mSds3 by active Cdk5 increases the homodimerization potential of mSds3. SIGNOR-262739 0.281 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-270065 0.2 PRKAB1 protein Q9Y478 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 t miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. SIGNOR-277609 0.2 ADRA1A protein P35348 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257195 0.435 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270379 0.8 KIF2C protein Q99661 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272529 0.7 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 0.374 NBR1 protein Q14596 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. SIGNOR-184267 0.741 SRC protein P12931 UNIPROT NECTIN2 protein Q92692 UNIPROT unknown phosphorylation Tyr505 EGEEEEEyLDKINPI -1 10962558 t miannu An inhibitor specific for Src family kinase or expression of Csk reduced tyrosine phosphorylation of nectin-2delta. In addition, Src kinase tyrosine phosphorylates the recombinant cytoplasmic region of nectin-2delta in vitro. The major tyrosine phosphorylation site of nectin-2delta was Tyr505 in the cytoplasmic region SIGNOR-263200 0.2 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates activity transcriptional regulation 10090 PMC3619734 f areggio Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1induction. SIGNOR-254990 0.2 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates activity phosphorylation Ser571 RDTYSDRsGSSSPDS 9606 BTO:0000007 17681942 t miannu Mutation of Ser-571 demonstrated that Ser-571 was the major site phosphorylated by GSK3 in intact human embryonic kidney 293 cells by GSK3 in vitro. Furthermore, mutation of Ser-575 prevented the phosphorylation of Ser-571, suggesting that phosphorylation of Ser-575 was necessary for priming the GSK3 phosphorylation of Ser-571. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. SIGNOR-276070 0.2 CNR1 protein P21554 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256724 0.541 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 0.517 C4A protein P0C0L4 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t complement C4b fragment: PRO_0000005970 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex SIGNOR-263400 0.624 MAPK1 protein P28482 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007;BTO:0000150 21502402 t gcesareni We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells. SIGNOR-173401 0.304 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 0.531 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser21 KEEPKRRsARLSAKP 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76282 0.307 linifanib chemical CHEBI:91435 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-258243 0.8 ARHGAP30 protein Q7Z6I6 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-260486 0.403 ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255933 0.444 MST1 protein P26927 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277178 0.2 GRIA2 protein P42262 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-264948 0.8 PRKN protein O60260 UNIPROT SEPTIN5 protein Q99719 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 14559152 t miannu SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains.Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins. SIGNOR-272673 0.2 RAP1GDS1 protein P52306 UNIPROT RHOC protein P08134 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc SIGNOR-171399 0.298 CRYGC protein P07315 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 f The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. SIGNOR-253624 0.7 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 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 9731215 t inferred from 70% family members lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. SIGNOR-270182 0.2 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Thr291 EDEESYDtESEFTEF 9606 BTO:0000782 8622692 t llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. SIGNOR-40514 0.581 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 0.343 BAZ1B protein Q9UIG0 UNIPROT MDC1 protein Q14676 UNIPROT down-regulates 9606 20965415 f gcesareni H2ax tyr142 is constitutively phosphorylated by the kinase wstf, a member of the baz/wal family of chromatin remodelling enzymes, and blocks mdc1 recruitment SIGNOR-168831 0.363 MRPS31 protein Q92665 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-261445 0.709 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266477 0.8 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248299 0.445 CLIP1 protein P30622 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 t lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) SIGNOR-264830 0.7 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 0.303 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 0.476 MAPKAPK5 protein Q8IW41 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 32690100 t miannu Consequently, our study clearly determined that p38 MAP kinase-activated MK5 could trigger the activity of c-Jun through phosphorylation of c-Jun, which then bound to the SNAI1 promoter to promote SNAI1-mediated EMT.It has been reported that altering extracellular responses and intracellular signal transduction, such as enhancing the activity of p38MAPK [48], JNK [49] and eIF4 [39] signaling pathways, leads to carcinogenesis and aggravates metastasis.|Western blot analysis showed that MK5 could promote the phosphorylation of c-Jun S63 site and the expression of SNAI1 (Fig.\u00a05a). SIGNOR-279422 0.383 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176606 0.8 MAPK3 protein P27361 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 t 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-147174 0.42 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 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-118584 0.489 NAA35 protein Q5VZE5 UNIPROT NatC complex SIGNOR-C417 SIGNOR form complex binding 9606 19398576 t miannu We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation. SIGNOR-267234 0.761 PXN protein P49023 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR up-regulates activity relocalization 16493410 t lperfetto Integrin-linked kinase (ILK), and isoforms of particularly interesting Cys-His-rich protein (PINCH) and parvin form the IPP complex (Fig. 2) in the cytoplasm, and this complex is recruited to focal adhesions through interactions with other factors, such as paxillin. SIGNOR-265767 0.581 FLT3 protein P36888 UNIPROT RAD51 protein Q06609 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-261550 0.251 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 0.834 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 t miannu PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266308 0.307 PLK1 protein P53350 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates activity phosphorylation 9606 33288550 t miannu Phosphorylation of the astrin N-terminal domain by Plk1 contributes to kinetochore\u2013microtubule attachment stability.|Taken together with the localisation data in XREF_FIG B, these data suggest that the presence of the Plk1 phosphorylated astrin N-terminus promotes the accumulation of the astrin complex at attached kinetochores, without which attachments appear more prone to dissociate. SIGNOR-279423 0.394 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser7 sSAEGAAK 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-76266 0.2 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by destabilization phosphorylation Ser265 PRSSSNAsSVSTRLS 9606 BTO:0001109 28945225 t miannu Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268.  SIGNOR-277325 0.2 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser29 WLKDQELsPREPVLP 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275591 0.2 JAK2 protein O60674 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity phosphorylation 9606 21907792 t miannu From these results, it can be concluded that JAK2 negatively regulates ERalpha protein level.We next analyzed by which mechanisms JAK2 could regulate ERalpha protein level.|We investigated whether JAK2 phosphorylates ER\u03b1 resulting in its ubiquitination and proteasomal degradation. SIGNOR-278949 0.435 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH1 protein P12830 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-265841 0.8 silodosin chemical CHEBI:135929 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258450 0.8 S1PR1 protein P21453 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-256856 0.504 CALM1 protein P0DP23 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-114098 0.751 PRKACA protein P17612 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr34 MIRRRRPtPAMLFRL 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-250031 0.504 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 0.436 CD55 protein P08174 UNIPROT ADGRE5 protein P48960 UNIPROT up-regulates binding 9606 BTO:0000142 12417446 t gcesareni This interaction may facilitate cell activation and migration through the blood-brain barrier. In addition, cd97-cd55 interactions in the parenchyma of the brain may contribute to the inflammation. SIGNOR-95458 0.2 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268075 0.8 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 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR aspartic acid smallmolecule CHEBI:22660 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270373 0.8 LIMK2 protein P53671 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates activity phosphorylation Ser185 KTKRKQLsSELGDLE 9606 34066036 t miannu LIMK2 also downregulates NKX3.1 mRNA levels.|While WT-NKX3.1 was efficiently phosphorylated, the S185A mutant showed no phosphorylation ( xref A), confirming that LIMK2 only phosphorylates the S185 site in NKX3.1. SIGNOR-278951 0.2 SHANK3 protein Q9BYB0 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-264607 0.7 PRKDC protein P78527 UNIPROT TOP1 protein P11387 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 GDHLHNDsQIEADFR 9606 BTO:0002201 28415827 t miannu Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.  SIGNOR-277352 0.448 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 0.2 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 0.2 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264732 0.2 IL6 protein P05231 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260256 0.7 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr454 VRGFPTIyFSPANKK -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262895 0.2 NDUFS8 protein O00217 UNIPROT NADH-ubiquinone oxidoreductase-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 0.853 Normorphine chemical CHEBI:7633 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-258822 0.8 MAPK8 protein P45983 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 10090 BTO:0001086 24913968 t SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation SIGNOR-251101 0.445 LIMK2 protein P53671 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity phosphorylation 9606 30716360 t miannu LIMK2 directly phosphorylated TWIST1, indicating that LIMK2 also regulates TWIST1 post-translationally (XREF_FIG).|LIMK2 positively regulates TWIST1 protein levels. SIGNOR-278952 0.2 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1. SIGNOR-252892 0.652 LRRK2 protein Q5S007 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity phosphorylation Ser176 KWRMMSLsQSRSSKS 9606 27830463 t miannu Altogether, our results indicate a scenario that LRRK2 physically interacts with Rip2 and promotes phosphorylation of Rip2.|Taken together, our results show that LRRK2 enhances Rip2 activity by promoting the phosphorylation of Rip2 at Ser176. SIGNOR-278953 0.376 EP300 protein Q09472 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR form complex binding 10116 BTO:0002648 12697832 t Giulio Giuliani More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex. SIGNOR-255418 0.453 KDM3A protein Q9Y4C1 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276845 0.2 CTSS protein P25774 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256323 0.309 ATM protein Q13315 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity phosphorylation Ser124 IIPNFQIsQDSVGNS 9606 27195665 t miannu We further confirm that RNF138 is phosphorylated by ATM at Ser124. SIGNOR-279505 0.2 ACSS2 protein Q9NR19 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271827 0.8 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 0.571 AKT3 protein Q9Y243 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251626 0.485 ATG3 protein Q9NT62 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) SIGNOR-141926 0.873 CHMP7 protein Q8WUX9 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-265525 0.618 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 0.671 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-270367 0.8 CDK2 protein P24941 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser47 DGPGLERsPGEPGGA 9606 27991597 t miannu Sirt1 is in turn phosphorylated by Cdk2, which may further regulate its activity.|Taken together, these data demonstrate that Cdk2 deletion does not decrease Hif1\u03b1 expression induced by HX, and strongly suggests that the phosphorylation of Sirt1 at Ser47 by Cdk2 requires Sirt1 deacetylase activity. SIGNOR-279513 0.465 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 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/cdk4 SIGNOR-62365 0.718 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 0.629 TFEB protein P19484 UNIPROT ATP6V0E1 protein O15342 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276534 0.31 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-265804 0.251 FOXA1 protein P55317 UNIPROT NFIB protein O00712 UNIPROT up-regulates binding 9606 24801505 t miannu Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex. SIGNOR-205027 0.314 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 10587640 t gcesareni Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21. SIGNOR-72882 0.489 DENND3 protein A2RUS2 UNIPROT RAB12 protein Q6IQ22 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.|active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy. SIGNOR-264734 0.624 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 17289999 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-152929 0.825 MDM2 protein Q00987 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 12821780 t miannu We could prove that Mdm2 physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in an in vitro assay. SIGNOR-278571 0.66 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr336 SKQSPIStPTSPGSL 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250660 0.405 SRC protein P12931 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni C-src was suggested to be involved in bmk1 activation from the experiments with herbimycin a and pp2, specific inhibitors of src family kinases. SIGNOR-113779 0.344 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 0.347 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates binding 9606 21295084 t gcesareni Mtch2/mimp and its role in bid recruitment may synergise with cl-induced mitosome formation to facilitate momp. SIGNOR-171773 0.303 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 0.682 SLC46A1 protein Q96NT5 UNIPROT heme smallmolecule CHEBI:30413 ChEBI up-regulates quantity relocalization 9606 BTO:0000575 32621820 t lperfetto SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes. SIGNOR-268265 0.8 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 0.271 ATF6 protein P18850 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 31226023 f miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260182 0.7 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269248 0.428 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 0.608 EPN1 protein Q9Y6I3 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-260716 0.661 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 0.2 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 0.304 PAK2 protein Q13177 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser9 NYLRRRLsDSNFMAN 10116 12237306 t miannu Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. SIGNOR-250236 0.326 NLGN3 protein Q9NZ94 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-264142 0.84 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275958 0.2 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 0.8 PRKACA protein P17612 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity phosphorylation 9606 28934360 t miannu Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G). SIGNOR-279649 0.283 TAOK1 protein Q7L7X3 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 9786855 t lperfetto The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway SIGNOR-60818 0.578 TNF protein P01375 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254809 0.2 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 0.586 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 0.449 NOD2 protein Q9HC29 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000567 19898471 f miannu Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. SIGNOR-252403 0.7 MAPK14 protein Q16539 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 f Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). SIGNOR-251838 0.2 MAPK4 protein P31152 UNIPROT DUSP2 protein Q05923 UNIPROT up-regulates activity phosphorylation 9606 28252035 t miannu However, co-expression of ERK4 significantly increased the half-life of DUSP2 (XREF_FIG).|In support of the latter notion we have shown that wild-type ERK4 can phosphorylate DUSP2 in vitro and future studies will be aimed at identifying the relevant site (s) of modification and determining their influence on DUSP2 stability. SIGNOR-278959 0.353 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 t Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. SIGNOR-268870 0.42 ERG protein P11308 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19396168 f miannu ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. SIGNOR-253911 0.2 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12707358 t lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-217442 0.376 BAG1 protein Q99933 UNIPROT HSPA8 protein P11142 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0001538 11676916 t miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association SIGNOR-272589 0.895 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269095 0.8 TFIID complex SIGNOR-C343 SIGNOR TFIIA complex SIGNOR-C395 SIGNOR up-regulates activity relocalization 9606 8990153 t lperfetto PIC assembly begins with TFIID recognizing the TATA element, followed by coordinated accretion of TFIIB, the nonphosphorylated form of pol II (pol IIA) plus TFIIF, TFIIE, and TFIIH. SIGNOR-269307 0.617 bethanechol chemical CHEBI:3084 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258624 0.8 SRC protein P12931 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation 9606 BTO:0002181 26198631 t miannu YY1 phosphorylation is mediated by Src family kinases. SIGNOR-276940 0.284 PTK2 protein Q05397 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Tyr174 QKASAPTyPSLYSSY 9606 BTO:0000007 22493428 t miannu  In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. SIGNOR-276410 0.274 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. SIGNOR-251005 0.328 STK17A protein Q9UEE5 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 t gcesareni Genetic and biochemical studies have shown that ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed dna-dependent p53 acetylation and b-cell tumor suppression. a cell-free ser20 phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser20 kinases. SIGNOR-153532 0.286 ARID1A protein O14497 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270729 0.788 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 0.2 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 0.884 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser293 SSGYFSSsPTLSSSP 9606 22017875 t llicata Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome. SIGNOR-176849 0.755 SOX9 protein P48436 UNIPROT MITF protein O75030 UNIPROT up-regulates activity binding 10090 20530484 t miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255183 0.383 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser831 EPVEQDSsQPSLPLV 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-197615 0.873 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 BTO:0000671 18075500 t gcesareni Gw788388 is a new tgf-beta type i receptor inhibitor with a much improved pharmacokinetic profile compared with sb431542. SIGNOR-159863 0.8 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 0.489 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp638 KLVFFAEdVGSNKGA -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-261764 0.489 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269375 0.726 RAB3C protein Q96E17 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 31679900 f miannu Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons.  SIGNOR-264376 0.7 MAPK1 protein P28482 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates phosphorylation Ser74 DKATQTLsPASPSQG 9606 BTO:0000785 22258404 t llicata Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf. SIGNOR-195471 0.253 NR5A1 protein Q13285 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-254871 0.479 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268277 0.8 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser364 LQSPITTsPSC 9606 10617468 t lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. SIGNOR-73625 0.805 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 0.2 MAPK3 protein P27361 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Ser21 KRTSSPRsPPSSSEI 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264773 0.2 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Ser408 DYTTGGEsCDELEED 9606 BTO:0002043 12804768 t llicata Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin. SIGNOR-251079 0.416 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 16440056 f lperfetto A second cytoplasmic dynein complex, cytoplasmic dynein 2, has a role in intraflagellar transport (IFT), a process required for ciliary/flagellar assembly SIGNOR-265022 0.7 IKBKE protein Q14164 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation 9606 29425491 t miannu While IKK\u03b5 phosphorylates and activates PDE3B to induce catecholamine resistance, TBK1 inhibits AMPK activity to reduce catabolism via this pathway. SIGNOR-278517 0.2 FOXA2 protein Q9Y261 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14739090 f lperfetto The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. SIGNOR-268987 0.2 PRKCB protein P05771 UNIPROT CYTH2 protein Q99418 UNIPROT down-regulates activity phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 t lperfetto ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'. SIGNOR-249024 0.307 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 0.361 ESCRT-III complex SIGNOR-C379 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 22361144 f miannu In vivo and in vitro data suggest a key role for the ESCRT-III complex in all ESCRT-mediated membrane remodeling (budding and scission) reactions, although the mechanism is not understood. Hence, ESCRT-III filaments may have a dual role during MVB sorting: cargo sequestration within the site of MVB vesicle formation and membrane budding/scission. SIGNOR-280934 PTPN2 protein P17706 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 12612081 f acerquone We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling. SIGNOR-252640 0.357 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 0.2 ESCRT-I complex, VPS37A-UBAP1 variant complex SIGNOR-C607 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 22361144 f miannu In vivo and in vitro data suggest a key role for the ESCRT-III complex in all ESCRT-mediated membrane remodeling (budding and scission) reactions, although the mechanism is not understood. Hence, ESCRT-III filaments may have a dual role during MVB sorting: cargo sequestration within the site of MVB vesicle formation and membrane budding/scission. SIGNOR-280935 ESCRT-II complex complex SIGNOR-C608 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 22361144 f miannu In vivo and in vitro data suggest a key role for the ESCRT-III complex in all ESCRT-mediated membrane remodeling (budding and scission) reactions, although the mechanism is not understood. Hence, ESCRT-III filaments may have a dual role during MVB sorting: cargo sequestration within the site of MVB vesicle formation and membrane budding/scission. SIGNOR-280936 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 0.387 alanine smallmolecule CHEBI:16449 ChEBI Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity precursor of 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270452 0.8 VEPH1 protein Q14D04 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 SIGNOR-269858 0.2 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-101306 0.34 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 0.444 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 0.2 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 0.733 PPM1A protein P35813 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity dephosphorylation Ser536 SGDEDFSsIADMDFS 9606 23812431 t lperfetto We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-kappaB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1 and chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis.|18 Wild-type, but not phosphatase-dead, PPM1A dephosphorylated the pS536 peptide with equivalent efficacy as the known RelA S536 phosphatase, Wip1 (XREF_FIG, compare lanes 4 and 7).|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA. SIGNOR-276964 0.353 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270866 0.635 CHEK1 protein O14757 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT down-regulates activity phosphorylation Ser251 RRLRRSHsGPAGSFN -1 22505024 t miannu Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1. SIGNOR-276411 0.326 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 0.423 MAOB protein P27338 UNIPROT (R)-adrenaline smallmolecule CHEBI:28918 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 t Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. SIGNOR-269746 0.8 AMPA proteinfamily SIGNOR-PF58 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f inferred from family member Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by na√Øve ones. SIGNOR-267783 0.7 RORA protein P35398 UNIPROT NLGN1 protein Q8N2Q7 UNIPROT up-regulates quantity by expression transcriptional regulation 28608249 t lperfetto Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005). SIGNOR-265136 0.2 PDGFRB protein P09619 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation 9606 15994317 t miannu The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2.|We conclude that the activated PDGFRbeta itself phosphorylates GRK2 tyrosyl residues and thereby activates GRK2, which then serine phosphorylates and desensitizes the PDGFRbeta. SIGNOR-278972 0.2 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation 9606 31938050 t miannu These novel findings establish a direct connection between the ubiquitination of UCK1 by KLHL2 and phosphorylation of USP28 and UCK1 by ATM, which are involved in mediating drug resistance against 5'-AZA in AML patients. SIGNOR-279007 0.311 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 0.509 DYRK1A protein Q13627 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 16959772 t lperfetto In vitro kinase assay of anti-dyrk1a immunocomplexes demonstrated that dyrk1a could phosphorylate alpha-synuclein at ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by dyrk1a, potentially affecting neuronal cell viability. SIGNOR-149393 0.561 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 0.2 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 0.762 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 0.2 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 0.554 ATIC protein P31939 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267325 0.8 CDK8 protein P49336 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273175 0.2 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 0.2 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 0.472 SLC1A6 protein P48664 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). SIGNOR-264805 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 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-249574 0.2 FYN protein P06241 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates phosphorylation Tyr353 NAQEKMVySLVSVPE 9606 14761954 t lperfetto We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm). SIGNOR-121795 0.487 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 0.268 ESCRT-III complex SIGNOR-C379 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 22361144 f miannu In vivo and in vitro data suggest a key role for the ESCRT-III complex in all ESCRT-mediated membrane remodeling (budding and scission) reactions, although the mechanism is not understood. Hence, ESCRT-III filaments may have a dual role during MVB sorting: cargo sequestration within the site of MVB vesicle formation and membrane budding/scission. SIGNOR-280937 FYN protein P06241 UNIPROT MED28 protein Q9H204 UNIPROT up-regulates phosphorylation Tyr64 ASLVSQDyVNGTDQE 9606 BTO:0001271;BTO:0000661 16899217 t fstefani To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro. SIGNOR-148700 0.446 JNK proteinfamily SIGNOR-PF15 SIGNOR BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f inferred from 70% family members gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. SIGNOR-269977 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 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-120188 0.316 Caspase 6 complex complex SIGNOR-C228 SIGNOR CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 t gcesareni This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8. SIGNOR-256468 0.735 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 0.8 SAGA complex complex SIGNOR-C465 SIGNOR H3-4 protein Q16695 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-269638 0.2 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 0.2 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 0.2 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 0.789 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 0.601 SGK1 protein O00141 UNIPROT KMT2D protein O14686 UNIPROT down-regulates activity phosphorylation Ser1331 RGRARLKsTASSIET 9606 BTO:0002181 30943409 t miannu  Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity.  SIGNOR-277447 0.283 TWIST1 protein Q15672 UNIPROT FOS protein P01100 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-255526 0.48 ZMYND8 protein Q9ULU4 UNIPROT NAV2 protein Q8IVL1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 21620140 t Luana We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.  SIGNOR-266209 0.2 ESCRT-I complex, VPS37A-UBAP1 variant complex SIGNOR-C607 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 22361144 f miannu In vivo and in vitro data suggest a key role for the ESCRT-III complex in all ESCRT-mediated membrane remodeling (budding and scission) reactions, although the mechanism is not understood. Hence, ESCRT-III filaments may have a dual role during MVB sorting: cargo sequestration within the site of MVB vesicle formation and membrane budding/scission. SIGNOR-280938 FYN protein P06241 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation 9606 26848862 t miannu FYN phosphorylates FLT3 on tyrosine residues (A\u2013B) COS1 cells were transfected with plasmids expressing FLT3 wild-type and FYN wild-type or mutants.|It was not completely unexpected that FYN associates wild-type FLT3 in the absence of ligand stimulation in COS-1 cells, as overexpression of wild-type FLT3 results in ligand independent activation of FLT3 (data not shown). SIGNOR-279715 0.292 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 10090 8387505 t lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases SIGNOR-252762 0.731 glutamic acid smallmolecule CHEBI:18237 ChEBI AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity chemical activation 9606 15919192 t miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264696 0.8 PYGB protein P11216 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267952 0.8 PRKCB protein P05771 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249122 0.353 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 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-268596 0.2 ALDH1A1 protein P00352 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265122 0.8 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 10116 9371779 t ggiuliani As shown in Fig. 2, immunoprecipitation of Smad8 with an anti-myc antibody could bring down the Flag-tagged Smad4 only in the presence of CA-ALK-2, indicating that only activation of ALK-2 but not ALK-4 could induce the heteromerization of Smad8 with Smad4. SIGNOR-255776 0.685 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr445 ANDVPSPyEVRGFPT -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262894 0.2 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. SIGNOR-138916 0.341 ATR protein Q13535 UNIPROT BLM protein P54132 UNIPROT up-regulates activity phosphorylation 9606 11916980 t miannu It is noteworthy that an active BLM seems to be unnecessary to the activation of BRCA1, either after gamma-rays or HU, even though BRCA1 and BLM helicase are activated by ATR in response to stalled replication, and despite the fact that they colocalize after replication arrest.|These results show that BLM phosphorylation by ATR after replication fork arrest is not important for its relocalization. SIGNOR-278978 0.852 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr118 VGEEEHVySFPNKQK 9606 15688067 t miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. SIGNOR-28243 0.914 HNRNPA2B1 protein P22626 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24792867 f miannu Hnrnpa2/b1 protein directly interacts with the r1 and r2 regions ofcdk5r13_-utr and displays a negative regulatory activity on its expression SIGNOR-205023 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2039 GLGQVGIsPLKPGTV 9606 BTO:0000551 24530506 t miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  SIGNOR-276458 0.2 ESCRT-II complex complex SIGNOR-C608 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 22361144 f miannu In vivo and in vitro data suggest a key role for the ESCRT-III complex in all ESCRT-mediated membrane remodeling (budding and scission) reactions, although the mechanism is not understood. Hence, ESCRT-III filaments may have a dual role during MVB sorting: cargo sequestration within the site of MVB vesicle formation and membrane budding/scission. SIGNOR-280939 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 0.2 belinostat chemical CHEBI:61076 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-257956 0.8 MBD1 protein Q9UIS9 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 f Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. SIGNOR-254036 0.251 RAN protein P62826 UNIPROT XPO1 protein O14980 UNIPROT up-regulates activity binding 31075303 t Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV lperfetto The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins SIGNOR-275848 0.928 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 0.524 GALR3 protein O60755 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-256998 0.278 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 0.8 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 0.7 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 0.8 CSNK1D protein P48730 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 t gcesareni Cki_/_ binds and phosphorylates lef-1, and this phosphorylation disrupts lef-1_-catenin interaction SIGNOR-134494 0.25 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser341 KALASIYsPDHSSNN 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161523 0.2 RPGRIP1 protein Q96KN7 UNIPROT RPGR protein Q92834 UNIPROT down-regulates activity binding 9606 20631154 t miannu The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments. SIGNOR-253031 0.714 DOCK1 protein Q14185 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001909 25533347 t miannu We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth. SIGNOR-266822 0.735 CD19 protein P15391 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 10090 BTO:0000776 25673924 f lperfetto CD19 is a crucial regulator of B cell activation. SIGNOR-242888 0.7 CDK1 protein P06493 UNIPROT LBR protein Q14739 UNIPROT down-regulates phosphorylation Ser71 KGGSTSSsPSRRRGS 9606 14718546 t lperfetto The binding of the nk fragment to chromatin pretreated with an s-phase extract was suppressed by incubation with an m-phase extract. Enzyme inhibitor experiments revealed that multiple kinases participate in the suppression. One of these kinases was shown to be cdc2 experiments involving a mutant nk fragment showed that the phosphorylation of serine 71 by cdc2 kinase is responsible for the suppression. SIGNOR-121335 0.396 PFKFB3 protein Q16875 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity chemical modification 9606 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267260 0.8 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser337 IVSPPPSsPPSSLTT 9606 8087847 t lperfetto Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. SIGNOR-36026 0.7 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 0.2 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN -1 11510412 t miannu Direct phosphorylation of B-Raf by PKA exerts a negative effect on its kinase activity, essentially via phosphorylation of Ser429 SIGNOR-250339 0.635 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates transcriptional regulation 9606 19254573 f fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation SIGNOR-210037 0.325 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 0.8 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 0.225 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 0.8 ERG protein P11308 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25277175 f miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. SIGNOR-251556 0.334 NXF2-NXT1 mRNA nuclear export factor complex complex SIGNOR-C610 SIGNOR mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 25628361 f miannu The NXF1:NXT1 complex (also known as TAP:p15) is a general mRNA nuclear export factor that is conserved from yeast to humans.  SIGNOR-280942 PRKCD protein Q05655 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-115722 0.342 CSNK2A1 protein P68400 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-250929 0.307 IKBKB protein O14920 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 9606 30478303 t miannu Here , we show that IKKbeta modulates the activity of p53 in response to glutamine depletion to promote cancer cell adaptation .|Taken together, these results indicate that IKK\u03b2 phosphorylates p53 on Ser392 as an early response to glutamine deprivation and possibly later facilitates its phosphorylation at Ser15 and transcriptional activity. SIGNOR-278516 0.52 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 BTO:0000944 14592976 t inferred from 70% family members lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) SIGNOR-270139 0.2 AP3M1 protein Q9Y2T2 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260682 0.872 STAT5A protein P42229 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 25506346 t lperfetto The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5 SIGNOR-249508 0.287 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 0.474 PRKAA1 protein Q13131 UNIPROT GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser122 GAKRVIIsAPSADAP 10090 26626483 t Luana  Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.  SIGNOR-259857 0.293 POFUT1 protein Q9H488 UNIPROT NOTCH1 protein P46531 UNIPROT 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-104627 0.745 PKA proteinfamily SIGNOR-PF17 SIGNOR PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276894 0.2 ERO1A protein Q96HE7 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-261049 0.2 MRPL58 protein Q14197 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-262344 0.2 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 0.2 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249464 0.633 C-to-U editosome complex complex SIGNOR-C611 SIGNOR mRNA_modification phenotype SIGNOR-PH239 SIGNOR up-regulates 9606 12881431 f miannu The C to U editing of apolipoprotein B (apoB) mRNA is mediated by a minimal complex composed of an RNA-binding cytidine deaminase (APOBEC1) and a complementing specificity factor (ACF). This editing generates a premature termination codon and a truncated open reading frame. We demonstrate that the APOBEC1-ACF holoenzyme mediates a multifunctional cycle.  SIGNOR-280947 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT Alamandine chemical CID:44192273 PUBCHEM up-regulates activity catalytic activity -1 24389733 t Luana Newly discovered peptide, alamandine, have been identified. Alamandine is generated by catalysis of Ang A via ACE2 or directly from Ang-(1–7). SIGNOR-262307 0.8 PYCARD protein Q9ULZ3 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256405 0.651 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 0.8 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 0.313 USP9X protein Q93008 UNIPROT UBA52 protein P62987 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-270825 0.611 AMPK complex SIGNOR-C15 SIGNOR ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 17097062 t lperfetto Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp. SIGNOR-216519 0.2 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 0.375 PHLPP1 protein O60346 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 21986499 t gcesareni Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP. SIGNOR-237454 0.572 RHCE protein P18577 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266022 0.321 POLR2K protein P53803 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266168 0.827 PRKCB protein P05771 UNIPROT MSX2 protein P35548 UNIPROT up-regulates quantity phosphorylation Thr141 CTLRKHKtNRKPRTP 9606 22633971 t miannu PKCbeta increased the level of overexpressed Msx2, but PKC alpha, delta and zeta did not have any significant effects.|Thr135 and Thr141 in Msx2 can be phosphorylated by PKC\u03b2, and Thr135 is important for regulating the protein stability of Msx2 by PKCs. SIGNOR-278983 0.322 PRKG2 protein Q13237 UNIPROT SOX9 protein P48436 UNIPROT down-regulates activity phosphorylation 9606 19543319 t miannu Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines|Prkg2 transfected glioma cell lines express a functional cGKII that can phosphorylate VASP and Sox9. SIGNOR-278985 0.501 PTK2 protein Q05397 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation 9606 25472995 t miannu Inhibition of FAK by its small molecule inhibitor attenuated IL-33-induced tyrosine 216 phosphorylation of GSK3beta in a both time- and dose dependent manner (XREF_FIG).|The current study indicates that FAK activated GSK3beta modulates ST2L internalization and signaling. SIGNOR-278986 0.365 MYO5A protein Q9Y4I1 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 21077886 f miannu Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis SIGNOR-269279 0.7 PRKCA protein P17252 UNIPROT ACO1 protein P21399 UNIPROT down-regulates phosphorylation Ser711 REFNSYGsRRGNDAV 9606 BTO:0000671 15636585 t gcesareni Irp1 ser-711 is a phosphorylation site, critical for regulation of rna-binding and aconitase activities. SIGNOR-133188 0.2 RAB7A protein P51149 UNIPROT ALS2 protein Q96Q42 UNIPROT down-regulates activity binding 9606 BTO:0000567 30485418 t miannu The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis SIGNOR-277778 0.305 Av/b5 integrin complex SIGNOR-C178 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-257723 0.649 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 0.651 LTF protein P02788 UNIPROT ITLN1 protein Q8WWA0 UNIPROT up-regulates activity binding 9606 23921499 t Intelectin 1 (IntL) is known as a lectin expressed in intestinal epithelia and also as a receptor for an iron-binding protein, lactoferrin (LF).  SIGNOR-272500 0.362 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity phosphorylation Ser593 NYKELKRsLENPAER 10090 BTO:0002572 21765415 t The effect has been demonstrated using Q86VP1-2 lperfetto Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, But not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1). SIGNOR-175058 0.383 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser717 LKEAEEEsSEDD 9606 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250989 0.37 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 0.467 SGK1 protein O00141 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Thr23 EMRERLGtGGFGNVC 9606 19088076 t miannu SGK1 directly phosphorylates IKKalpha at Thr 23 and indirectly activates IKKalpha at Ser 180.|SGK1 directly phosphorylates IKKalpha at Thr-23 and indirectly activates IKKalpha at Ser-180. SIGNOR-278987 0.26 MYOD1 protein P15172 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241100 0.702 SGK1 protein O00141 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates quantity phosphorylation Ser104 LTFDSSFsPNTGKKN 9606 30929899 t miannu As hypothesized based upon our observation that activated SGK-1 reduces VDAC-1 protein levels, sgk-1 overexpression normalizes the shortened lifespan of vdac-1 transgenics .|Taken together, these data indicate that Ser104 phosphorylation of VDAC1 by SGK1 increases its ubiquitination and subsequent cellular clearance. SIGNOR-278988 0.2 SRC protein P12931 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation 9606 24196445 t miannu Using mass spectrometry we identified 9 Src-mediated Tyr-phosphorylation sites within HIPK2, 5 of them positioned in the kinase domain.|We demonstrate that ectopic expression of Src increases the half-life of HIPK2 by interfering with Siah-1-mediated HIPK2 degradation. SIGNOR-278989 0.307 TNC protein P24821 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR up-regulates activity binding 9606 BTO:0001521 38058842 t miannu TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells. SIGNOR-277735 0.43 tacrolimus (anhydrous) chemical CHEBI:61049 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-252308 0.8 TIM22 complex complex SIGNOR-C424 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 32901109 f lperfetto The TIM22 complex is responsible for the translocation and insertion of hydrophobic membrane proteins, including mitochondrial carrier proteins and translocase subunits (Tim17, Tim22 and Tim23) SIGNOR-267710 0.7 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 0.764 CPLANE1 protein Q9H799 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 35740972 f miannu Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and RSG1 for cilia formation.  SIGNOR-280953 CPLANE2 protein Q9BU20 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 35740972 f miannu Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and RSG1 for cilia formation.  SIGNOR-280954 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 0.2 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 11160424 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-104939 0.8 NFE2L2 protein Q16236 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 t miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254652 0.45 GSK3B protein P49841 UNIPROT USF2 protein Q15853 UNIPROT up-regulates activity phosphorylation Ser155 NPFSNGGsPAAEAVS 9606 25238393 t miannu Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.|First, it was found that GSK3beta phosphorylates USF2 at S155 and T230. SIGNOR-278157 0.283 AIM2 inflammasome complex SIGNOR-C222 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256382 0.2 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 0.255 GNA12 protein Q03113 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates activity binding 9606 BTO:0000007 11546812 t Marta Tosoni These data suggest that G12 is an upstream activator of AKAP-Lbc in the Rho signaling pathway. SIGNOR-278882 0.524 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser122 PKPPPAAsPGVRAGH -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277878 0.2 GSK3B protein P49841 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation Ser163 PDKQFLIsPPASPPV 10090 BTO:0000165 12063245 t lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. SIGNOR-249359 0.484 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation Thr312 QATQPLAtPVVSVTT 9606 9858528 t lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a SIGNOR-62780 0.661 NDUFB9 protein Q9Y6M9 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262172 0.812 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser221 DLDRIAAsMRALVLR -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1. SIGNOR-178128 0.904 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates activity phosphorylation Thr217 LEPEALHtPTLMTTP 9606 27816489 t Manara PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. SIGNOR-260878 0.2 STK25 protein O00506 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation 9606 30948712 t miannu Collectively, our data demonstrate that loss of STK25 promotes YAP/TAZ activation.|Lastly, we assessed if STK25 is able to promote YAP phosphorylation in the absence of LATS-HM phosphorylation, based on our in vitro kinase assay results. SIGNOR-278993 0.265 PTEN protein P60484 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr179 FQNRRYKtKRKQLSS 9606 31213464 t lperfetto Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression.|PTEN was also able to dephosphorylate NKX3.1 at threonine 179, a target of protein kinase C, but not threonine residues 89 and 93, targeted by casein kinase 2 . SIGNOR-277026 0.441 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t miannu Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-260095 0.2 CDK1 protein P06493 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Thr34 FLEGCACtPERMAEA 9606 11861764 t gcesareni Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo SIGNOR-115129 0.686 ZFYVE26 protein Q68DK2 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. FYVE-CENT binds directly to TTC19 and KIF13A. SIGNOR-265542 0.462 HMGA2 protein P52926 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 25300915 f miannu This study unraveled a novel function ofhmga2in induction of apoptosis in human primary cell lines SIGNOR-205465 0.7 GPR37 protein O15354 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 12666095 f lperfetto Parkin-associated endothelin receptor-like receptor (Pael-R). Overexpression of this protein causes it to become ubiquinated, insoluble, and unfolded, leading to endoplasmic reticulum stress and cell death. Furthermore, an insoluble form of Pael-R has been demonstrated to accumulate in the brains of patients with Parkin mutations, suggesting a possible toxic mechanism. SIGNOR-249701 0.7 CIITA protein P33076 UNIPROT HLA-DOA protein P06340 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-254005 0.335 GSK3B protein P49841 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 RPPSPSAsPASEKSM 9606 BTO:0000498 31289136 t miannu GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. SIGNOR-277465 0.2 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270460 0.8 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12626569 t 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-99119 0.436 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 14657019 t gcesareni Arkadia physically interacts with inhibitory smad, smad7, and induces its poly-ubiquitination and degradation. SIGNOR-119663 0.736 RNF183 protein Q96D59 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29507230 t miannu As an E3 ligase, RNF183 ubiquitinates Bcl-xL, causing its degradation and subsequent apoptosis. SIGNOR-278595 0.385 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 0.8 CLTB protein P09497 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260671 0.77 YBX1 protein P67809 UNIPROT TYMS protein P04818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001023 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255613 0.247 MAP2K1 protein Q02750 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 23360980 t miannu In addition, though MEK-1 was able to induce C-Raf phosphorylation at the S338 site, which was shown to play a role in C-Raf activation by certain growth factors [ xref ], MEK-1 was able to bind and activate the S338/339A C-Raf mutant, suggesting that the MEK-1-induced C-Raf activation does not require phosphorylation at these sites ( xref , lanes 4, 5, left panel and lanes 6\u20139, right panel).|MEK-1-induced C-Raf activation is Ras independent. SIGNOR-279627 0.749 MAP3K1 protein Q13233 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity phosphorylation 9606 27806347 t miannu As a result, MEKK1 suppresses the Notch1 intracellular domain protein stability and transcriptional activity.|We confirmed that MEKK1 binds to Notch1 intracellular domain and phosphorylates the Notch1 intracellular domain Threonine 2512 residue. SIGNOR-279628 0.367 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 0.552 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 0.7 PPP2CA protein P67775 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates dephosphorylation 9606 15467457 t miannu Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation. SIGNOR-129752 0.581 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser932 DDTPEKDsFRARSTS 9606 BTO:0002181 30684133 t miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. SIGNOR-277426 0.2 STK26 protein Q9P289 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Thr83 KTANVPQtVPMRLRK 9606 32271880 t miannu Further, and consistent with our aforementioned finding that MST4 inactivates YAP in response to serum starvation, this stress condition enhanced the YAP\u2013MST4 interaction ( xref ).|Here, we revealed that the MST4 kinase-mediated Thr83 phosphorylation of YAP represents such an additional mechanism of YAP inactivation. SIGNOR-278994 0.2 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 t Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity. SIGNOR-255309 0.363 phenformin chemical CHEBI:8064 ChEBI KCNJ11 protein Q14654 UNIPROT down-regulates activity chemical inhibition 9606 20188727 t lperfetto Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). SIGNOR-262031 0.8 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBG1 protein P23258 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-259259 0.8 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI TEK protein Q02763 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194349 0.8 CSNK2A1 protein P68400 UNIPROT CEBPD protein P49716 UNIPROT up-regulates activity phosphorylation Ser57 PAMYDDEsAIDFSAY -1 25680545 t miannu Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.  SIGNOR-276886 0.2 CDK1 protein P06493 UNIPROT HMGA2 protein P52926 UNIPROT down-regulates phosphorylation Ser59 PKGSKNKsPSKAAQK 9606 10636877 t lperfetto Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone. SIGNOR-74098 0.374 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1230 RHSLAARyYNWVSFP 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104072 0.2 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257450 0.8 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258570 0.8 GOLGA7 protein Q7Z5G4 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 t miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. SIGNOR-261354 0.396 SSTR5 protein P35346 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256969 0.28 TGFB2 protein P61812 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates binding 9606 10746731 t gcesareni Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors. SIGNOR-76473 0.518 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-268102 0.8 EIF2S2 protein P20042 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269115 0.956 FBXW7 protein Q969H0 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 11585921 t gcesareni We show here that the f-box/wd40 repeat protein sel-10 negatively regulates notch receptor activity by targeting the intracellular domain of notch receptors for ubiquitin-mediated protein degradation. in conclusion, hsel-10 physically associates with mouse notch4(int-3) through the wd40 domain, whereas the f-box domain is not required for this interaction. SIGNOR-110955 0.499 TPR protein P12270 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 t miannu Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20). SIGNOR-181918 0.486 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 LKRASFAkSVIGTPE 9606 12374799 t Manara Activation of WNKs requires autophosphorylation of at least one serine residue, serine 382 in WNK1, within the WNK activation loop. SIGNOR-260826 0.2 SUPT7L protein O94864 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269585 0.668 AKT1 protein P31749 UNIPROT GATA2 protein P23769 UNIPROT down-regulates phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t PI-3K/Akt-dependent manner. fspada We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-135614 0.524 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 0.2 SMARCE1 protein Q969G3 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270612 0.836 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 12970777 t gcesareni The raf inhibitor l-779,450. This raf inhibitor was less effective on b-raf- or mek1-responsive cells, demonstrating the specificity of this drug. SIGNOR-100358 0.8 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 0.586 FYN protein P06241 UNIPROT CNN3 protein Q15417 UNIPROT down-regulates activity phosphorylation Tyr261 SQKGMSVyGLGRQVY 9534 BTO:0000298 15206927 t We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin SIGNOR-251159 0.333 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 f areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy. SIGNOR-254994 0.7 PRKACA protein P17612 UNIPROT CHCHD3 protein Q9NX63 UNIPROT unknown phosphorylation Thr11 TTSTRRVtFEADENE -1 17242405 t miannu Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. we used the recombinant GST-ChChd3 for an in vitro kinase assays to determine whether in vitro phosphorylation by PKA was direct. Fig. 6 demonstrates that PKA directly phosphorylates recombinant Chchd3 with a stoichiometry of 0.3 mol of phosphate incorporated per mol of ChChd3. Although three potential PKA phosphorylation sites exist in ChChd3, Thr10 represents the most likely site to be phosphorylated. SIGNOR-263116 0.2 TTK protein P33981 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity phosphorylation -1 18541701 t miannu Furthermore, although catalytically inactive Mps1 can restore kinetochore localization of Mad1, only the active kinase restores Mad2 localization.|Indeed, Mps1 can phosphorylate Mad1 in vitro. SIGNOR-279000 0.819 SOSTDC1 protein Q6X4U4 UNIPROT WNT5B protein Q9H1J7 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242727 0.276 XPO1 protein O14980 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity relocalization 9606 17891139 t 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-260067 0.549 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser745 SCLADSFsQAADEEE 9606 BTO:0000150 10910365 t llicata Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45 SIGNOR-79876 0.828 CDK1 protein P06493 UNIPROT CLASP2 protein O75122 UNIPROT up-regulates activity phosphorylation Ser1234 QGYDNSEsSVRKACV 9606 23045552 t miannu Overall, these results support the idea that phosphorylation of CLASP2 on S1234 by Cdk1, but not phosphorylation of the CLASP2 C terminal by Plk1, is required to maintain mitotic spindle bipolarity.|We propose that Cdk1 and Plk1 mediate a CLASP2 phospho-switch that is necessary to stabilize KT-MT attachments in human cells. SIGNOR-278233 0.569 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258090 0.8 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16239 0.577 KDM5C protein P41229 UNIPROT SCN2A protein Q99250 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-264313 0.329 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258734 0.8 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 0.2 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244916 0.755 SRC protein P12931 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity phosphorylation Tyr284 EELAMDVyDEVDRRE 9534 BTO:0000298 24699139 t miannu Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. SIGNOR-276627 0.542 APC protein P25054 UNIPROT ODC1 protein P11926 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12112318 t APC-dependent regulation of ornithine decarboxylase in human colon tumor cells|Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed SIGNOR-253670 0.268 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t Gianni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131577 0.2 GLIS1 protein Q8NBF1 UNIPROT WNT5A protein P41221 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32047936 t miannu GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A SIGNOR-269040 0.248 NLGN3 protein Q9NZ94 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-264189 0.755 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 BTO:0000782;BTO:0000801 17095509 t gcesareni We found that in these cells, lipopolysaccharide stimulates the expression of mhc ii genes via the activation of erk1/2, which is mediated by toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of ciita isoform 1 that leads to its monoubiquitylation. SIGNOR-150545 0.341 EEF1A1 protein P68104 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269512 0.8 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr444 TKSSKSStPVPSKQS 9606 16247472 t lperfetto Here we show that two mitotic kinases, cdk1 and polo-like kinase 1 (plk1), phosphorylate ect2 in vitro.Moreover, ect2 t412a, but not phosphomimic t412d, displayed a diminished accumulation of gtp-bound rhoa compared with wt ect2, suggesting that phosphorylation of thr-412 is critical for the catalytic activity of ect2. SIGNOR-141175 0.577 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 7779757 t Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. SIGNOR-269748 0.8 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 0.546 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264872 0.264 SRGAP3 protein O43295 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 12447388 t miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95967 0.553 Y-27632 chemical CHEBI:75393 ChEBI ROCK2 protein O75116 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207893 0.8 ITF complex complex SIGNOR-C613 SIGNOR Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 22118932 f miannu The process of Intraflagellar Transport (IFT) is of central importance for both the assembly and maintenance of cilia, as it delivers building blocks from their site of synthesis in the cell body to the ciliary assembly site at the tip of the cilium. SIGNOR-280961 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 0.744 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 0.37 SRPK2 protein P78362 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation 9606 33602301 t miannu In contrast, SRPK1 or SRPK2 overexpression upregulated the phosphorylation and nucleus accumulation of SRSF1.|Therefore, SRPK1 and SRPK2 may directly phosphorylate SRSF1 and promote it nucleus translocation, subsequently modulate MKNK2 alternative splicing. SIGNOR-279660 0.616 FAM20C protein Q8IXL6 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates activity phosphorylation Ser47 ELVLALRsEEDGLAE 9606 31553664 t miannu Herein, we report that Fam20C and Fam20A significantly eliminate the Furin-cleavage of PCSK9 (XREF_FIG, lanes 5, 6), thereby enhancing the pPCSK9 activity|Herein, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668 and 688. SIGNOR-278935 0.537 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 0.269 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 0.8 Ile(5)-angiotensin II smallmolecule CHEBI:2719 ChEBI AGTR1 protein P30556 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257459 0.8 ATM protein Q13315 UNIPROT MPG protein P29372 UNIPROT up-regulates activity phosphorylation Ser172 YFCMNISsQGDGACV 9606 25100205 t miannu ATM phosphorylates MPG at serine 172 (XREF_FIG).|In summary, our results show that ATM and MPG are directly associated in vitro and in vivo, phosphorylation of MPG at serine 172 is dependent on ATM and that of loss of phospho ATM reduces MPG glycosylase activity. SIGNOR-279004 0.265 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 11163210 t lperfetto Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. SIGNOR-104999 0.71 APC-c complex SIGNOR-C150 SIGNOR TK1 protein P04183 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 14701726 t miannu We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. SIGNOR-272946 0.248 NUMB protein P49757 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates binding 9606 20940030 t gcesareni Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53 SIGNOR-168454 0.444 GPHN protein Q9NQX3 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity by stabilization binding 10116 BTO:0000938 21994384 t miannu we demonstrate that GABA(A)Rs and gephyrin are intimately associated at inhibitory synapses in cultured rat neurons. Our results suggest that the direct binding of gephyrin to residues 360-375 of the α1 subunit and its modulation are likely to be important determinants for the stabilization of GABA(A)Rs at synaptic sites, thereby modulating the strength of synaptic inhibition. SIGNOR-264964 0.2 PRKCA protein P17252 UNIPROT PLCB1 protein Q9NQ66 UNIPROT unknown phosphorylation Ser887 HSQPAPGsVKAPAKT 10090 BTO:0005065 11278470 t lperfetto . Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation. SIGNOR-249081 0.714 SAMM50 protein Q9Y512 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 t lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. SIGNOR-267683 0.807 TFE3 protein P19532 UNIPROT CD63 protein P08962 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276812 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269368 0.726 CDK1 protein P06493 UNIPROT NUSAP1 protein Q9BXS6 UNIPROT down-regulates phosphorylation Thr300 HKRSLTKtPARKSAH 9606 22101338 t llicata We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo. SIGNOR-177545 0.431 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 0.354 PKN1 protein Q16512 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-275461 0.384 EGFR protein P00533 UNIPROT SCAMP1 protein O15126 UNIPROT up-regulates activity phosphorylation Tyr37 VPPGLDEyNPFSDSR -1 9658162 t miannu In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation SIGNOR-262857 0.335 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-122075 0.828 ATM protein Q13315 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity phosphorylation Ser547 MDFSALLsQISS 9606 24957606 t miannu Interestingly, another group has identified that in the VP-16 induced NF-\u03baB activation, ATM binds to RelA directly and phosphorylates RelA on Ser 547, a post-translational modification that represses a subset of NF-\u03baB-dependent genes ( xref ).|Our findings that ablation of ATM reduces RelA serine 276 phosphorylation, suggests a mechanism for how ROS mediates RelA serine 276 phosphorylation in the TNF pathway (Figure -D). SIGNOR-279006 0.502 EGFR protein P00533 UNIPROT TLR3 protein O15455 UNIPROT up-regulates activity phosphorylation Tyr858 FLEEIPDyKLNHALC 9606 25022196 t miannu Although both the ErbB1 and the ErbB2 isoforms of EGFR can bind to activated TLR3, functionally, only ErbB1 can trigger TLR3 signaling.|There is a high degree of specificity of the targets of the two PTKs, EGFR and Src SIGNOR-278932 0.426 MAPK13 protein O15264 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114075 0.2 PNPLA6 protein Q8IY17 UNIPROT 2-(((R)-2,3-Dihydroxypropyl)phosphoryloxy)-N,N,N-trimethylethanaminium smallmolecule CID:439285 PUBCHEM up-regulates quantity chemical modification 9606 25033069 t PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus SIGNOR-253611 0.8 Mitochondrial pyruvate carrier complex complex SIGNOR-C614 SIGNOR pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity relocalization 9606 40691140 t miannu The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells.  SIGNOR-280964 DVL2 protein O14641 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates activity binding 10029 BTO:0000457 23132247 t gcesareni Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions. SIGNOR-243999 0.269 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 0.367 COL1A1 protein P02452 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253247 0.568 MAPK8 protein P45983 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates phosphorylation Ser95 TSSSSATsPASASFK 9606 17023523 t llicata We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity. SIGNOR-149998 0.5 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163266 0.698 CHUK protein O15111 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 15808510 t miannu These results demonstrated an estrogen-mediated increase in the phosphorylation of ER\u03b1 at serine residue 118 by IKK\u03b1 ( Figure 5 H, bottom).|Wt IKKalpha, but not the IKKalpha kinase mutant, increased both estrogen dependent and -independent ERalpha activation. SIGNOR-279696 0.47 MRPL14 protein Q6P1L8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262379 0.654 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 0.697 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270431 0.8 NKX2-5 protein P52952 UNIPROT TBX5 protein Q99593 UNIPROT up-regulates quantity by expression transcriptional regulation 15095414 f Mutation at the potential TBE-B and -C sites, and at the GC box and NKX2.5 sites significantly decreased luciferase activity, suggesting that the GC box and the potential TBE-B, -C, and NKX2.5 sites are functionally important for the activation of the promoter function. SIGNOR-253650 0.769 CSNK1E protein P49674 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation 9606 18991847 t miannu CKIepsilon phosphorylates and activates DARPP-32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence. SIGNOR-279701 0.322 RSPO3 protein Q9BXY4 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t gcesareni Here, we show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling. SIGNOR-172756 0.422 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 0.952 SARM1 protein Q6SZW1 UNIPROT TICAM1 protein Q8IUC6 UNIPROT down-regulates binding 10090 17667936 t gcesareni SARM utilizes its TIR domain to negatively regulate TRIF SIGNOR-252068 0.53 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 16613856 t lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation SIGNOR-227550 0.458 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg391 SPSFIQIrSVAKKHP -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-263642 0.454 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 9445476 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-55371 0.609 regorafenib chemical CHEBI:68647 ChEBI PDGFRA protein P16234 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-259179 0.8 ING1 protein Q9UK53 UNIPROT CASP3 protein P42574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 f miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. SIGNOR-254489 0.258 LNX1 protein Q8TBB1 UNIPROT BCR protein P11274 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 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-272903 0.267 EGFR protein P00533 UNIPROT GLUD1 protein P00367 UNIPROT up-regulates activity phosphorylation Tyr135 SWEVIEGyRAQHSQH 9606 36516759 t miannu EGFR phosphorylates GDH1 at Y135 and contributes to GDH1 activation.|Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. SIGNOR-279706 0.2 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr468 DSGISTDySSGDSQG 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-251352 0.812 NXF2-NXT2 mRNA nuclear export factor complex complex SIGNOR-C615 SIGNOR mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 23754955 f miannu The highly conserved, Nxf/Nxt (TAP/p15) RNA nuclear export pathway is important for export of most mRNAs from the nucleus, by interacting with mRNAs and promoting their passage through nuclear pores.  SIGNOR-280975 NXF5-NXT1 mRNA nuclear export factor complex complex SIGNOR-C616 SIGNOR mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 23754955 f miannu The highly conserved, Nxf/Nxt (TAP/p15) RNA nuclear export pathway is important for export of most mRNAs from the nucleus, by interacting with mRNAs and promoting their passage through nuclear pores.  SIGNOR-280976 NXF3-NXT1 mRNA nuclear export factor complex complex SIGNOR-C618 SIGNOR mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 23754955 f miannu The highly conserved, Nxf/Nxt (TAP/p15) RNA nuclear export pathway is important for export of most mRNAs from the nucleus, by interacting with mRNAs and promoting their passage through nuclear pores.  SIGNOR-280977 NXF5-NXT2 mRNA nuclear export factor complex complex SIGNOR-C619 SIGNOR mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 23754955 f miannu The highly conserved, Nxf/Nxt (TAP/p15) RNA nuclear export pathway is important for export of most mRNAs from the nucleus, by interacting with mRNAs and promoting their passage through nuclear pores.  SIGNOR-280978 PLK1 protein P53350 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates activity phosphorylation Ser312 ASLKRSPsASSLSSM -1 24451569 t lperfetto Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment|Here, we show that phosphorylation at Ser312 in the third serine-rich region of CLIP-170 is increased during mitosis. Polo-like kinase 1 (Plk1) is responsible for this phosphorylation during the mitotic phase of dividing cells. In vitro analysis using a purified CLIP-170 N-terminal fragment showed that phosphorylation by Plk1 diminishes CLIP-170 binding to the MT ends SIGNOR-264575 0.703 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 0.512 FOXA2 protein Q9Y261 UNIPROT AHSG protein P02765 UNIPROT up-regulates quantity by expression transcriptional regulation 16595698 f lperfetto CCAAT enhancer binding protein beta and hepatocyte nuclear factor 3beta are necessary and sufficient to mediate dexamethasone-induced up-regulation of alpha2HS-glycoprotein/fetuin-A gene expression. SIGNOR-271676 0.234 MYOD1 protein P15172 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241122 0.673 GPR183 protein P32249 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256715 0.418 2-oxoglutaric acid smallmolecule CHEBI:30915 ChEBI OXGR1 protein Q96P68 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257555 0.8 GRK2 protein P25098 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity phosphorylation Ser18 LKKLSEDsLTKQPEE 9606 23904266 t miannu Taken together, these studies support a role for GRK2 phosphorylation of Mst2 residues Ser-18 and Ser-316 in EGF-promoted centrosome separation.|Thus GRK2 appears to mediate EGF promoted cleavage and activation of Mst2. SIGNOR-278207 0.2 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 0.8 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 0.288 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 15210796 t gcesareni We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-126250 0.432 MTA3 protein Q9BTC8 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-263852 0.785 CALM3 protein P0DP25 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266340 0.525 NXF3-NXT2 mRNA nuclear export factor complex complex SIGNOR-C620 SIGNOR mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 23754955 f miannu The highly conserved, Nxf/Nxt (TAP/p15) RNA nuclear export pathway is important for export of most mRNAs from the nucleus, by interacting with mRNAs and promoting their passage through nuclear pores.  SIGNOR-280979 SMO protein Q99835 UNIPROT OPALIN protein Q96PE5 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 f Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. SIGNOR-269225 0.2 ZBED1 protein O96006 UNIPROT RPS6 protein P62753 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 t Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. SIGNOR-266082 0.2 ADORA1 protein P30542 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257092 0.335 FGFR4 protein P22455 UNIPROT STK4 protein Q13043 UNIPROT down-regulates activity phosphorylation 9606 30903103 t miannu FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2 dependent apoptosis.|We provide evidence suggesting that by Y433-MST1 phosphorylation , FGFR4 inhibits MST1 / 2 activation . SIGNOR-279714 0.2 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 0.962 FGF13 protein Q92913 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253427 0.269 SIN3B protein O75182 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity binding 9606 BTO:0001109 26181367 t miannu The present study shows that under bleomycin-induced stress, expression of Sin3B gets up-regulated and it gets recruited by p53 at its target promoters. Knockdown of Sin3B leads to impaired negative regulation of p53 target genes and thus exemplifies Sin3B as a critical player in down-regulation of p53 subset target genes. SIGNOR-266776 0.497 RAB3GAP1 protein Q15042 UNIPROT RAB3A protein P20336 UNIPROT down-regulates activity gtpase-activating protein 10116 BTO:0000142 11809763 t miannu Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). SIGNOR-265580 0.439 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236266 0.793 HSP90AA1 protein P07900 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 18591668 t lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. SIGNOR-179271 0.384 NFIX protein Q14938 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268906 0.2 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269325 0.435 PRDM1 protein O75626 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 f SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. SIGNOR-269263 0.7 LATS1 protein O95835 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr285 EDKMKHCtKIQVIDI -1 34465890 t miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. SIGNOR-276506 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 t inferred from 70% family members lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-270198 0.2 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TNF protein P01375 UNIPROT down-regulates quantity BTO:0000801 22933625 f apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255446 0.7 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 t gcesareni In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72687 0.462 SB 203580 chemical CHEBI:90705 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 BTO:0000222 15208625 t fstefani Pharmacological blockade of p38?/? Kinases by sb203580 inhibits the myogenic program3_5 by repressing the transcription of early (myogenin;myog) and late (muscle-creatine kinase;ckm) muscle genes in myoblasts induced to differentiate SIGNOR-126052 0.8 CDC25C protein P30307 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity dephosphorylation 9606 25949173 t miannu Cdc25C is an activator of Cdc2 kinase and dephosphorylates and activates the CyclinB-Cdc2 complex shortly before the entry into the mitosis. SIGNOR-277099 0.832 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin SIGNOR-182844 0.481 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 0.8 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser70 LTKSERYsSSGSPAN 9606 BTO:0000093 35513296 t miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings SIGNOR-277908 0.341 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. SIGNOR-81149 0.429 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 0.326 FGA protein P02671 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 7679388 t gcesareni To map the binding sites for four distinct ligands for mac-l: ic3b, fibrinogen, icam-1. __the i domain on the ot chain of mac-1 is an important recognition site for all four ligands. SIGNOR-31320 0.387 ME2 protein P23368 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267054 0.8 NEK1 protein Q96PY6 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates phosphorylation Ser193 DGTEFGGsIYQKVNK 9606 20230784 t lperfetto Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux. SIGNOR-164222 0.424 CDK1 protein P06493 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates phosphorylation Thr2055 MAFSILNtPKKLGNS 9606 23921553 t llicata Cdk1-mediated phosphorylation at t2055 negatively regulates numa cortical localization and that this phosphorylation is counteracted by ppp2ca phosphatase activity. SIGNOR-194825 0.587 estrone smallmolecule CHEBI:17263 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258583 0.8 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT down-regulates activity phosphorylation Ser163 KENPRNFsDNQLQEG 21577206 t lperfetto This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity. SIGNOR-265105 0.315 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262979 0.312 CDK5 protein Q00535 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Ser131 HTDSRKDsPPAGSPA 9606 BTO:0000142 17327227 t llicata Phosphorylation by cdk5 decreased the auto-ubiquitylation of parkin both in vitro and in vivo. SIGNOR-153445 0.2 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-101302 0.403 JMJD1C protein Q15652 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 BTO:0000007 32034158 t miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. SIGNOR-265331 0.2 CDK1 protein P06493 UNIPROT TAZ protein Q16635 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 26183396 t miannu Our studies suggest that phosphorylation and degradation of TAZ by Cdk1 may play important roles in apoptosis induced by antitubulin drugs. SIGNOR-278240 0.266 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258078 0.8 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser41 EAAGPAPsPMRAANR 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-250606 0.992 MAPK8IP3 protein Q9UPT6 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10523642 t gcesareni Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct. SIGNOR-71471 0.542 FHIT protein P49789 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis SIGNOR-252625 0.373 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr81 APAPAAPtPAAPAPA 9606 12531896 t gcesareni Wr1065 activates the jnk (c-jun n-terminal kinase), decreases complex formation between p53 and inactive jnk, and phosphorylates p53 at thr-81, a known site of phosphorylation by jnk. SIGNOR-97405 0.796 PIK3CG protein P48736 UNIPROT SET protein Q01105 UNIPROT up-regulates activity phosphorylation 9606 21419339 t miannu We show that PI3Kgamma phosphorylates I2PP2A on serine 9 and 93 residues resulting in enhanced interaction of I2PP2A with PP2A. SIGNOR-278320 0.336 R2SP co-chaperone complex SIGNOR-C517 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 29844425 f miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270941 0.7 TACR3 protein P29371 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256794 0.2 PRLHR protein P49683 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-256837 0.278 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 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-175291 0.763 Gbeta proteinfamily SIGNOR-PF4 SIGNOR AMPH protein P49418 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 15262992 t inferred from 70% family members lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-270102 0.2 PRKX protein P51817 UNIPROT SMAD6 protein O43541 UNIPROT up-regulates activity phosphorylation 9606 16491121 t miannu In vitro phosphorylation assays demonstrated that PrKX phosphorylates Smad6 at a serine residue. SIGNOR-279270 0.431 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT up-regulates quantity by expression transcriptional regulation 7957050 t lperfetto Using a DNA binding assay, a specific p53 binding site was identified upstream from the cyclin G gene, which functioned as a p53-dependent cis-acting element in a transient transfection assay. SIGNOR-268960 0.791 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 0.2 EP300 protein Q09472 UNIPROT MN1 protein Q10571 UNIPROT up-regulates binding 9606 12569362 t miannu Our results indicate that mn1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate rar/rxr-mediated transcription through interaction with p160 and p300. SIGNOR-97899 0.342 MTHFD2L protein Q9H903 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification 10116 21163947 t lperfetto Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified.  SIGNOR-268252 0.8 LRP5 protein O75197 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity relocalization 10090 11336703 t amattioni Axin is a protein that interacts with the intracellular domain of LRP-5. LRP-5 active form bind Axin and induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. SIGNOR-236997 0.83 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser801 VPLLREAsARDRQSA 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-249142 0.2 GSK3B protein P49841 UNIPROT SIK1 protein P57059 UNIPROT up-regulates activity phosphorylation 9606 18348280 t miannuccelli Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates Ser/Thr residues located at the fourth position ahead of the pre-phosphorylated Ser/Thr residues, and inhibitors of GSK-3beta reduce the phosphorylation at Thr182. The results of an in vitro reconstitution assay also indicate that GSK-3beta could be the SIK1 kinase. However, overexpression and knockdown of GSK-3beta in LKB1-defective HeLa cells suggests that GSK-3beta alone may not be able to phosphorylate or activate SIK1, indicating that LKB1 may play a crucial role by phosphorylating SIK1 at Thr182, possibly as an initiator of the autophosphorylation cascade, and GSK-3beta may phosphorylate SIK1 at Thr182 by recognizing the priming-autophosphorylation at Ser186 in cultured cells. SIGNOR-279742 0.2 ITCH protein Q96J02 UNIPROT SPART protein Q8N0X7 UNIPROT up-regulates activity binding 9606 BTO:0000567 20719964 t Sara SPG20 Protein Spartin Is Recruited to Midbodies by ESCRT-III Protein Ist1 and Participates in Cytokinesis. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells significantly decreases the number of cells where spartin is present at midbodies. SIGNOR-261308 0.2 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 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-248658 0.377 FRZB protein Q92765 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, SIGNOR-51798 0.484 FFAR1 protein O14842 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256799 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI SYT1 protein P21579 UNIPROT up-regulates activity chemical activation 9606 16679567 t miannu Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion SIGNOR-263976 0.8 Tubulin polyglutamylase complex complex SIGNOR-C621 SIGNOR Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 34782749 f miannu Tubulin polyglutamylation levels are maintained by the tubulin glutamylase family of tubulin tyrosine ligase-like (TTLL) proteins and the cytosolic carboxypeptidases (CCPs), a family of tubulin deglutamylases. Tubulin polyglutamylase complex (TPGC) was the first protein complex identified with tubulin polyglutamylase activity. SIGNOR-280985 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR up-regulates quantity by expression 9606 29892818 f inferred from family member scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. SIGNOR-270243 0.8 PLK1 protein P53350 UNIPROT RANBP1 protein P43487 UNIPROT up-regulates activity phosphorylation 9606 21813642 t miannuccelli Here, we demonstrated in vitro and in vivo phosphorylation of RanBP1 by Plk1 as well as the importance of phosphorylation of RanBP1 in the interaction between Plk1 and Ran during early mitosis. SIGNOR-279751 0.359 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 0.287 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 0.617 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu63 VQGNLEReCMEEKCS 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-263689 0.683 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0002572 10026169 t lperfetto Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. SIGNOR-236512 0.709 PRKCE protein Q02156 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Thr200 LPMWSNQtWNNSTWS 9606 23708658 t miannu Taken together, our results demonstrate that PKC\u03b5-mediated phosphorylation at T200 and T280 enhances Nanog protein stability in head and neck squamous cell carcinoma.|These observations confirm that PKCepsilon modulates Nanog transcriptional activity and demonstrate that Nanog is phosphorylated by PKCepsilon at T200 and T280 in vivo. SIGNOR-278203 0.329 2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid chemical CHEBI:91634 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258806 0.8 CCP110 protein O43303 UNIPROT CETN3 protein O15182 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-265968 0.418 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267530 0.8 CDK5 protein Q00535 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates quantity phosphorylation Ser1116 YRRRPPRsPDHKRYF 9606 24607229 t miannu Cdk5 phosphorylates NR2B at Ser1116 and controls surface level expression.|Reduction in Cdk5 activity, as well as disruption of Cdk5-NR2B interactions consistently increased NR2B surface levels and facilitated NMDA mediated synaptic function. SIGNOR-278265 0.443 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. 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-216801 0.382 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 0.469 PRKCE protein Q02156 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates phosphorylation Ser782 PLEQYSPsYPDTRSS 9606 BTO:0000938 23564461 t lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation SIGNOR-201675 0.2 AKT1 protein P31749 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t gcesareni The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1. SIGNOR-124365 0.43 STK11 protein Q15831 UNIPROT PRMT5 protein O14744 UNIPROT up-regulates activity phosphorylation Thr139 TNLARVLtNHIHTGH -1 30289978 t miannu We found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1.  SIGNOR-277411 0.2 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 0.565 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 BTO:0000150 19567672 t llicata Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions SIGNOR-186467 0.479 PKA proteinfamily SIGNOR-PF17 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates activity phosphorylation Ser189 QEYTVKLsNIPTIKR 9534 12646569 t lperfetto Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. SIGNOR-264796 0.2 CDK1 protein P06493 UNIPROT SKA3 protein Q8IX90 UNIPROT up-regulates activity phosphorylation Thr358 SYENLLRtPTPPEVT 9606 28479321 t miannu Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization. SIGNOR-278376 0.394 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 0.533 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 0.8 UBE3A protein Q05086 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity ubiquitination 9606 18193166 t miannu E6-AP also directly ubiquitylated p53 in an in vitro ubiquitylation assay.|Our result suggests that E6-AP not only enhances the degradation of p53 but also regulates the neuronal cell growth. SIGNOR-278681 0.681 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 0.2 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 0.2 NAE complex SIGNOR-C131 SIGNOR CUL1 protein Q13616 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-243151 0.745 CTF1 protein Q16619 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12859689 f miannu CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. SIGNOR-252219 0.2 sulpiride chemical CHEBI:32168 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). SIGNOR-258431 0.8 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 0.7 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 0.897 IL4R protein P24394 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 BTO:0000776 7538655 f gcesareni The overlapping and distinct protein tyrosine phosphorylation and activation of the same jak1 kinase in t lymphocytes strongly suggests that il-4 and il-9 share the common signal transduction pathways. SIGNOR-28399 0.676 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251589 0.704 PRKCI protein P41743 UNIPROT VIM protein P08670 UNIPROT up-regulates activity phosphorylation Ser34 SRSYVTTsTRTYSLG 9606 BTO:0001033 33525953 t miannu Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells. SIGNOR-277623 0.2 DAPK1 protein P53355 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity phosphorylation Thr667 ILTGRGKtNQNTGMT 9606 BTO:0002181 28132841 t miannu DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5'ppp-dsRNA sensing and virtually abrogate RIG-I activation. SIGNOR-277336 0.33 PHKA1 protein P46020 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-267405 0.691 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 0.751 PCDHA11 protein Q9Y5I1 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-265670 0.2 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 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation 9606 19767751 t inferred from 70% family members gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-270041 0.2 HUWE1 protein Q7Z6Z7 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 31713291 t miannu Taken together, these results are consistent with our hypothesis that HUWE1 directly poly-ubiquitinates and targets Chk1 to the proteasome. SIGNOR-278568 0.298 CHKA protein P35790 UNIPROT KDR protein P35968 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 22711876 t miannu Here, we show for the first time a possible mechanism by which CKI dependent phosphorylation of VEGFR2 at specific sites in its C-terminal tail triggers SCF beta-TRCP -mediated VEGFR2 ubiquitination and destruction. SIGNOR-279029 0.249 AP2M1 protein Q96CW1 UNIPROT SLC24A2 protein Q9UI40 UNIPROT down-regulates quantity binding 9606 BTO:0000938 SIGNOR-C245 23431067 t miannu  we report that the first tyrosine motif of NCKX2 interacts with AP2M1 and that the interaction is required for endocytosis of NCKX2 from the dendritic surface. Furthermore, we show that a Src family kinase (SFK) modulates the endocytosis of NCKX2 by tyrosine-phosphorylation of the AP-2 recognition motif in NCKX2. SIGNOR-264388 0.2 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252569 0.763 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 0.8 AXIN1 protein O15169 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 16601693 t gcesareni Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. SIGNOR-145851 0.712 COL1A1 protein P02452 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000165 12496264 t lperfetto Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. SIGNOR-253345 0.583 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 0.68 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 0.819 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Thr183 RQADSEMtGYVVTRW 9606 19230643 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases SIGNOR-184134 0.659 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 0.416 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 0.2 LAMTOR1 protein Q6IAA8 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-164769 0.926 ropinirole chemical CHEBI:8888 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 9057850 t miannu Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively) SIGNOR-258601 0.8 IKBKB protein O14920 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates activity phosphorylation Ser123 RERQRTQsLNEAFAA 9606 23375009 t miannu Hence, our current study supports the pivotal role of beta-TRCP in IKKbeta mediated Twist degradation.|More importantly, IKKbeta dependent phosphorylation of Twist at T125 and S127 governs its nuclear localization. SIGNOR-278405 0.332 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 0.506 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser772 LVTPRKKsKSKLEEK -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-271842 0.2 CCNT1 protein O60563 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-130634 0.2 PKM protein P14618 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266536 0.8 TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 t lperfetto Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. SIGNOR-162638 0.597 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 0.2 SNX6 protein Q9UNH7 UNIPROT IGF2R protein P11717 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 t miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. SIGNOR-269443 0.364 panobinostat chemical CHEBI:85990 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-257755 0.8 CDC26 protein Q8NHZ8 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252011 0.851 MDM2 protein Q00987 UNIPROT KAT2B protein Q92831 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14769800 t miannu Consistently, overexpression of MDM2 in p53 null cells caused the reduction of the protein level of PCAF, but not the mRNA level.|MDM2 ubiquitinated PCAF in vitro and in cells. SIGNOR-278825 0.621 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 0.335 RIN1 protein Q13671 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 11784866 t gcesareni We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1. SIGNOR-113970 0.598 anastrozole chemical CHEBI:2704 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189614 0.8 PTPN1 protein P18031 UNIPROT STAM2 protein O75886 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr291 KSEPEPVyIDEDKMD 9606 20504764 t Together, the results presented here demonstrate that PTP1B can influence RTK signaling in a previously unrecognized manner. We show that PTP1B directly targets STAM2, part of the ESCRT-0 endosomal sorting complex, and we provide the first evidence that tyrosine phosphorylation affects STAM localization and function. This regulatory mechanism could impact signaling downstream of numerous cell surface receptors that are ubiquitinated and recognized by this conserved sorting machinery. SIGNOR-248406 0.472 PPP2CA protein P67775 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. SIGNOR-248650 0.309 TUBA3E protein Q6PEY2 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269726 0.7 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 0.668 DOK1 protein Q99704 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-257698 0.2 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser396 RPWTRGGsLERSQSR 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-248985 0.39 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248885 0.284 CENPQ protein Q7L2Z9 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265207 0.787 DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255881 0.2 MAPK8 protein P45983 UNIPROT SARM1 protein Q6SZW1 UNIPROT down-regulates activity phosphorylation Ser548 AAREMLHsPLPCTGG 30333228 t lperfetto C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration|Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity. SIGNOR-275554 0.423 SEH1L protein Q96EE3 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262092 0.624 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-184577 0.595 FAM13B protein Q9NYF5 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-260503 0.435 HOXB13 protein Q92826 UNIPROT TCF4 protein P15884 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 15928669 f miannu In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth.  SIGNOR-254476 0.2 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262999 0.529 WWTR1 protein Q9GZV5 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 22153608 t Activation of Wnt signaling induces the hyperphosphorylation of Dishevelled (DVL), and this, via a poorly understood mechanism, ultimately leads to a rise in beta-Catenin levels and to the activation of beta-Catenin target genes. gcesareni Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation. SIGNOR-195212 0.358 CAMKK1 protein Q8N5S9 UNIPROT CAMK1D protein Q8IU85 UNIPROT up-regulates activity phosphorylation Thr180 GKGDVMStACGTPGY BTO:0000567 12935886 t llicata CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. | This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells. SIGNOR-250715 0.416 SMARCD2 protein Q92925 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270603 0.725 CYSLTR2 protein Q9NS75 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257024 0.517 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton SIGNOR-266596 0.7 UBXN1 protein Q04323 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 15362974 f miannu Our working hypothesis is that SAKS1 acts as scaffolding protein to enhance the unfolding and proteolytic destruction of a subset of proteins. PNGase removes high-mannose-containing oligosaccharides from MGPs [30], and our results suggest this may be facilitated by the formation of a complex between PNGase, VCP, SAKS1 and ubiquitinated MGPs, as illustrated schematically in Figure 7(B). PNGase has been reported to bind to the S4 component of the proteasome [30], so that the deglycosylation of MGPs by PNGase, followed by VCP-catalysed unfolding, may facilitate their destruction by the proteasome. SIGNOR-261059 0.7 NLGN2 protein Q8NFZ4 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264161 0.829 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 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-269481 0.8 AURKA protein O14965 UNIPROT CEP192 protein Q8TEP8 UNIPROT up-regulates activity phosphorylation 9606 25042804 t lperfetto Thus, following their sequential activation in Cep192 complexes, both AurA and Plx1 phosphorylate Cep192.|We found that Cep192 1\u20131000 -wt promoted AurA and Plx1 activation and itself underwent phosphorylation irrespective of whether it was bound to the endogenous or recombinant Plx1 (i.e. whether Plx1 was docked onto T46 or not) (lanes 6 and 8). SIGNOR-279797 0.796 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134617 0.343 PSMB6 protein P28072 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263361 0.853 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser232 NRYGMGTsVERAAAS -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-252055 0.732 AKT proteinfamily SIGNOR-PF24 SIGNOR ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata Akt phosphorylates s554 in acap1 SIGNOR-141343 0.2 GAB2 protein Q9UQC2 UNIPROT PIK3CA protein P42336 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-204966 0.466 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IL17A protein Q16552 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 f miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology SIGNOR-263819 0.7 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 t ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 0.744 pazopanib hydrochloride chemical CHEBI:71217 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. SIGNOR-259167 0.8 PELI3 protein Q8N2H9 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity ubiquitination 9606 25526310 t miannu Finally, we used coexpression studies to directly demonstrate that Pellino3 inhibits the ability of wild-type TRAF6 to stabilize HIF-1alpha but not the stabilizing effects of the K124A TRAF6 mutant that is resistant to ubiquitination.|In the present study, Pellino3 ubiquitinates TRAF6 with lysine 63-linked polyubiquitin chains to block the interaction of TRAF6 with HIF-1\u03b1. SIGNOR-278707 0.63 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 22722787 t XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. gcesareni Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4). SIGNOR-197959 0.8 AURKA protein O14965 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 28114281 t lperfetto Conversely, AURKA can phosphorylate VHL at serine 72, a priming phosphorylation for GSK3beta, which regulates VHL 's role in microtubule stability. SIGNOR-279800 0.406 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1009 LDTSSVLyTAVQPNE -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248416 0.691 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249199 0.611 LPCAT2 protein Q7L5N7 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272764 0.8 EIF4A3 protein P38919 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265240 0.948 IL1A protein P01583 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 9767234 f miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252387 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA6 protein Q9Y5G7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265694 0.2 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Thr713 SKRNSVDtATSSSLS -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250884 0.329 EIF2B1 protein Q14232 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269124 0.83 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser723 VITIDPAsPQSPESV 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-111039 0.571 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Thr404 HYETDYTtGGESCDE 9606 12804768 t llicata Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin. SIGNOR-251080 0.416 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 0.399 POU4F1 protein Q01851 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity binding 9606 9448000 t 2 miannu The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect. SIGNOR-241275 0.552 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 10090 BTO:0000944 19171758 t miannu In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. SIGNOR-265554 0.739 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 0.8 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 0.2 RPS6KA3 protein P51812 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates quantity phosphorylation Ser789 DTRSSTCsSGEDSVF 9606 BTO:0001938 24141780 t miannu  Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity. SIGNOR-276599 0.357 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22459801 f miannu Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. SIGNOR-254644 0.342 PPARGC1A protein Q9UBK2 UNIPROT CYCS protein P99999 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253097 0.381 SEMA3A protein Q14563 UNIPROT PLXNA1 protein Q9UIW2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261813 0.77 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk SIGNOR-64172 0.637 ARNTL protein O00327 UNIPROT CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253627 0.933 IKBKB protein O14920 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 24290981 t miannu Taken together, these results indicate that IKK\u03b2-dependent phosphorylation of RAPGEF2 is required for RAPGEF2 degradation induced by HGF and mediated by \u03b2TrCP. SIGNOR-279805 0.2 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 0.366 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser221 VSPMPSTsEATTDED 9606 BTO:0000007 24396068 t miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  SIGNOR-276479 0.35 UBE2E3 protein Q969T4 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization sumoylation Lys21 EGPRDGLkKERLLDD 9606 BTO:0000007;BTO:0000567 10582246 t lperfetto In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation.  SIGNOR-270545 0.346 ATM protein Q13315 UNIPROT LARP7 protein Q4G0J3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr440 ANREECRtQEKVNAT 32726637 t lperfetto Altogether, the results suggest that ATM-mediated T440 phosphorylation enhances LARP7-BARD1 interaction and facilitates BRCA1/BARD1-mediated LARP7 ubiquitination and degradation. SIGNOR-275580 0.2 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1292 MTIGMHLsQAVKAGC -1 10608806 t llicata We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. SIGNOR-250578 0.826 RTKs proteinfamily SIGNOR-PF38 SIGNOR ITGB4 protein P16144 UNIPROT up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259031 0.2 POU5F1 protein Q01860 UNIPROT DLX5 protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254935 0.31 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190281 0.8 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248780 0.431 PTPN1 protein P18031 UNIPROT PTK6 protein Q13882 UNIPROT down-regulates activity dephosphorylation Tyr342 RLIKEDVyLSHDHNI 9606 29142193 t miannu Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342. SIGNOR-277082 0.575 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Lys76 YRLVSINkSSPLQKQ -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-263574 0.624 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-251037 0.307 P2RY11 protein Q96G91 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257173 0.2 NFE2L2 protein Q16236 UNIPROT PXDN protein Q92626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567; BTO:0000007 29953917 t miannu PXDN expression in response to H2O2 and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells.We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. SIGNOR-265248 0.2 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) SIGNOR-176483 0.341 PRKG2 protein Q13237 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser863 TSTLPRNsGAGASSG 9606 18728399 t miannu In cultured hippocampal neurons, activation of cGKII induces an accumulation of GluR1 on the cellular plasma membrane at extrasynaptic sites, and blockage of cGKII activity prevents the surface increase of GluR1, and also the increase in mEPSC frequency and amplitude, that follows a chemical form of LTP (chemLTP).|In this complex, cGKII phosphorylates GluR1 at serine 845 (S845), a site known to be phosphorylated also by PKA. SIGNOR-278427 0.44 PTK6 protein Q13882 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 23027128 t miannu B. PTK6 phosphorylates FAK at tyrosine residue 861.|Knockdown of PTK6 in the PC3 human prostate cancer cell line disrupts FAK and AKT activation and promotes anoikis, which can be rescued by exogenous expression of FAK. SIGNOR-278428 0.264 OGT protein O15294 UNIPROT TET1 protein Q8NFU7 UNIPROT up-regulates activity glycosylation 9606 BTO:0002181 23729667 t irozzo The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt. SIGNOR-259184 0.44 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 0.2 DHFR protein P00374 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268258 0.8 PDPK1 protein O15530 UNIPROT TSSK3 protein Q96PN8 UNIPROT up-regulates activity phosphorylation Thr168 SHRELSQtFCGSTAY -1 16336268 t Manara We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation. SIGNOR-260786 0.261 STAG2 protein Q8N3U4 UNIPROT RAD21 protein O60216 UNIPROT up-regulates quantity by stabilization binding 9606 28430577 t miannu Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-261511 0.965 DGUOK protein Q16854 UNIPROT 2'-deoxyinosine 5'-phosphate(2-) smallmolecule CHEBI:61194 ChEBI up-regulates quantity chemical modification 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280576 0.8 2'-deoxyinosine smallmolecule CHEBI:28997 ChEBI 2'-deoxyinosine 5'-phosphate(2-) smallmolecule CHEBI:61194 ChEBI up-regulates quantity precursor of 9606 17073823 t miannu DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor. SIGNOR-280577 0.8 TK2 protein O00142 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280578 0.8 TK2 protein O00142 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280579 0.8 TK2 protein O00142 UNIPROT 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI down-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280580 0.8 TK2 protein O00142 UNIPROT 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280581 0.8 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity precursor of 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280582 0.8 TK2 protein O00142 UNIPROT thymidine smallmolecule CHEBI:17748 ChEBI down-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280583 0.8 TK2 protein O00142 UNIPROT dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280584 0.8 thymidine smallmolecule CHEBI:17748 ChEBI dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity precursor of 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280585 0.8 TK2 protein O00142 UNIPROT 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI down-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280586 0.8 TK2 protein O00142 UNIPROT dUMP(2-) smallmolecule CHEBI:246422 ChEBI up-regulates quantity chemical modification 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280587 0.8 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI dUMP(2-) smallmolecule CHEBI:246422 ChEBI up-regulates quantity precursor of 9606 25215937 t miannu Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates.  SIGNOR-280588 0.8 UCKL1 protein Q9NWZ5 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280589 0.8 UCKL1 protein Q9NWZ5 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280590 0.8 UCKL1 protein Q9NWZ5 UNIPROT cytidine smallmolecule CHEBI:17562 ChEBI down-regulates quantity chemical modification 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280591 0.8 BTF3 protein P20290 UNIPROT MADCAM1 protein Q13477 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253945 0.2 UCKL1 protein Q9NWZ5 UNIPROT cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity chemical modification 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280592 0.8 cytidine smallmolecule CHEBI:17562 ChEBI cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity precursor of 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280593 0.8 UCKL1 protein Q9NWZ5 UNIPROT uridine smallmolecule CHEBI:16704 ChEBI down-regulates quantity chemical modification 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280594 0.8 UCKL1 protein Q9NWZ5 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280595 0.8 uridine smallmolecule CHEBI:16704 ChEBI uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity precursor of 9606 35583288 t miannu Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280596 0.8 UCK1 protein Q9HA47 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280597 0.8 UCK1 protein Q9HA47 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280598 0.8 UCK1 protein Q9HA47 UNIPROT cytidine smallmolecule CHEBI:17562 ChEBI down-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280599 0.8 UCK1 protein Q9HA47 UNIPROT cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280600 0.8 cytidine smallmolecule CHEBI:17562 ChEBI cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity precursor of 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280601 0.8 UCK1 protein Q9HA47 UNIPROT uridine smallmolecule CHEBI:16704 ChEBI down-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280602 0.8 UCK1 protein Q9HA47 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280603 0.8 uridine smallmolecule CHEBI:16704 ChEBI uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity precursor of 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280604 0.8 UCK2 protein Q9BZX2 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280605 0.8 UCK2 protein Q9BZX2 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280606 0.8 UCK2 protein Q9BZX2 UNIPROT cytidine smallmolecule CHEBI:17562 ChEBI down-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280607 0.8 UCK2 protein Q9BZX2 UNIPROT cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280608 0.8 cytidine smallmolecule CHEBI:17562 ChEBI cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity precursor of 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280609 0.8 UCK2 protein Q9BZX2 UNIPROT uridine smallmolecule CHEBI:16704 ChEBI down-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280610 0.8 UCK2 protein Q9BZX2 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280611 0.8 uridine smallmolecule CHEBI:16704 ChEBI uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity precursor of 9606 27239701 t miannu Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively.  SIGNOR-280612 0.8 PUDP protein Q08623 UNIPROT pseudouridine 5'-phosphate(2-) smallmolecule CHEBI:58380 ChEBI down-regulates quantity chemical modification 9606 20722631 t miannu Purified human recombinant HDHD1 dephosphorylated pseudouridine 5′-phosphate with a kcat of 1.6 s−1, a Km of 0.3 μM and a catalytic efficiency at least 1000-fold higher than that on which it acted on other phosphate esters, including 5′-UMP.  SIGNOR-280613 0.8 PUDP protein Q08623 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 20722631 t miannu Purified human recombinant HDHD1 dephosphorylated pseudouridine 5′-phosphate with a kcat of 1.6 s−1, a Km of 0.3 μM and a catalytic efficiency at least 1000-fold higher than that on which it acted on other phosphate esters, including 5′-UMP.  SIGNOR-280614 0.8 PUDP protein Q08623 UNIPROT pseudouridine smallmolecule CHEBI:17802 ChEBI up-regulates quantity chemical modification 9606 20722631 t miannu Purified human recombinant HDHD1 dephosphorylated pseudouridine 5′-phosphate with a kcat of 1.6 s−1, a Km of 0.3 μM and a catalytic efficiency at least 1000-fold higher than that on which it acted on other phosphate esters, including 5′-UMP.  SIGNOR-280615 0.8 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 0.286 pseudouridine 5'-phosphate(2-) smallmolecule CHEBI:58380 ChEBI pseudouridine smallmolecule CHEBI:17802 ChEBI up-regulates quantity precursor of 9606 20722631 t miannu Purified human recombinant HDHD1 dephosphorylated pseudouridine 5′-phosphate with a kcat of 1.6 s−1, a Km of 0.3 μM and a catalytic efficiency at least 1000-fold higher than that on which it acted on other phosphate esters, including 5′-UMP.  SIGNOR-280616 0.8 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr823 DIKNDSNyVVKGNAR 9606 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. / tyr-823 is the last tyrosine residue to be autophosphorylated SIGNOR-102641 0.2 UPP1 protein Q16831 UNIPROT 2-deoxy-D-ribofuranose 1-phosphate(2-) smallmolecule CHEBI:58576 ChEBI down-regulates quantity chemical modification 9606 21855639 t miannu Uridine phosphorylase (UPP) catalyzes the reversible conversion of uridine to uracil and ribose-1-phosphate and plays an important pharmacological role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil and capecitabine. Most vertebrate animals, including humans, possess two homologs of this enzyme (UPP1 & UPP2), of which UPP1 has been more thoroughly studied and is better characterized SIGNOR-280534 0.8 TK1 protein P04183 UNIPROT dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity chemical modification 9606 17407781 t miannu The two dTTP biosynthetic routes are the de novo and the salvage pathways. Human thymidine kinase 1 (hTK1) catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. SIGNOR-280518 0.8 NODAL protein Q96S42 UNIPROT TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 f Regulation miannu Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway. SIGNOR-251942 0.661 thymidine smallmolecule CHEBI:17748 ChEBI dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity precursor of 9606 17407781 t miannu The two dTTP biosynthetic routes are the de novo and the salvage pathways. Human thymidine kinase 1 (hTK1) catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. SIGNOR-280520 0.8 UPP1 protein Q16831 UNIPROT 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI up-regulates quantity chemical modification 9606 21855639 t miannu Uridine phosphorylase (UPP) catalyzes the reversible conversion of uridine to uracil and ribose-1-phosphate and plays an important pharmacological role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil and capecitabine. Most vertebrate animals, including humans, possess two homologs of this enzyme (UPP1 & UPP2), of which UPP1 has been more thoroughly studied and is better characterized SIGNOR-280535 0.8 uracil smallmolecule CHEBI:17568 ChEBI 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI up-regulates quantity precursor of 9606 21855639 t miannu Uridine phosphorylase (UPP) catalyzes the reversible conversion of uridine to uracil and ribose-1-phosphate and plays an important pharmacological role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil and capecitabine. Most vertebrate animals, including humans, possess two homologs of this enzyme (UPP1 & UPP2), of which UPP1 has been more thoroughly studied and is better characterized SIGNOR-280536 0.8 UPP2 protein O95045 UNIPROT uracil smallmolecule CHEBI:17568 ChEBI down-regulates quantity chemical modification 9606 21855639 t miannu Uridine phosphorylase (UPP) catalyzes the reversible conversion of uridine to uracil and ribose-1-phosphate and plays an important pharmacological role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil and capecitabine. Most vertebrate animals, including humans, possess two homologs of this enzyme (UPP1 & UPP2), of which UPP1 has been more thoroughly studied and is better characterized SIGNOR-280537 0.8 UPP2 protein O95045 UNIPROT 2-deoxy-D-ribofuranose 1-phosphate(2-) smallmolecule CHEBI:58576 ChEBI down-regulates quantity chemical modification 9606 21855639 t miannu Uridine phosphorylase (UPP) catalyzes the reversible conversion of uridine to uracil and ribose-1-phosphate and plays an important pharmacological role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil and capecitabine. Most vertebrate animals, including humans, possess two homologs of this enzyme (UPP1 & UPP2), of which UPP1 has been more thoroughly studied and is better characterized SIGNOR-280538 0.8 ADAM10 protein O14672 UNIPROT BTC protein P35070 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin SIGNOR-259839 0.372 hypoxanthine smallmolecule CHEBI:17368 ChEBI 2'-deoxyinosine smallmolecule CHEBI:28997 ChEBI up-regulates quantity precursor of 9606 35063692 t miannu Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine salvage pathway. Inosine and guanosine and the respective deoxynucleosides are substrates of this enzyme. Adenosine and deoxyadenosine are mainly deaminated by adenosine deaminase respectively to inosine and deoxyinosine which are in turn catabolized by PNP SIGNOR-280556 0.8 CSNK1A1 protein P48729 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-250785 0.286 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 0.553 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276091 0.288 GMPS protein P49915 UNIPROT guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267338 0.8 8-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)butyl]-1H-quinolin-2-one chemical CHEBI:91585 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257857 0.8 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 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-258635 0.8 SRC protein P12931 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation 9606 26114632 t miannu In addition, the c-Src inhibitor 4-(4\u2019-phenoxyanilino)-6,7-dimethoxyquinazoline prevented SP-induced activation of HER2.|On the other hand, c-Src directly phosphorylates the cytoplasmic tails of both EGFR and HER2, allowing the binding of scaffold proteins that will further activate signal transduction. SIGNOR-279432 0.615 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr266 TDSIRDEyAFLQKKY 9606 29022905 t miannu Interestingly, we found that Drp1 was a substrate of c-Abl kinase and ectopic expression of c-Abl increased Drp1 's mitochondrial localization and GTPase activity.|c-Abl phosphorylates Drp1 at Y266, Y368 and Y449. SIGNOR-278462 0.26 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251523 0.2 SMARCC2 protein Q8TAQ2 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270746 0.843 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 0.483 PLAG1 protein Q6DJT9 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11888928 f miannu Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis SIGNOR-256658 0.7 RUNX1 protein Q01196 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity binding 9606 22021368 t apalma We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling SIGNOR-255690 0.2 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity precursor of 9606 20637175 t miannu 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-280568 0.8 SRMS protein Q9H3Y6 UNIPROT FKBP5 protein Q13451 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr54 PMIGDKVyVHYKGKL 9606 BTO:0000567 34077419 t miannu SRMS binds FKBP51 and phosphorylates tyrosine 54. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. SIGNOR-277564 0.267 LRIG1 protein Q96JA1 UNIPROT EGFR protein P00533 UNIPROT down-regulates binding 9606 BTO:0001253 15282549 t gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation SIGNOR-127304 0.736 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser317 TPQGSRTsPGAPPPA -1 15133517 t miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. SIGNOR-263060 0.2 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TFAP2C protein Q92754 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-269256 0.373 CCKBR protein P32239 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256765 0.264 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 0.8 IGF1R protein P08069 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000951 17200203 f Indirect:regulation of expression miannu Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts SIGNOR-251863 0.294 GSK3B protein P49841 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates activity phosphorylation Ser22 RSRQNPQsPPQDSSV 9606 20520769 t miannu GSK3beta was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3beta resulted in decreased binding of antibody to phosphoserine-22, a potential GSK3beta phosphorylation site in HDAC6.|This suggests that GSK3\u03b2 may directly phosphorylate HDAC6 at this site, although further work with purified proteins is needed to determine whether this is the case.|The fact that HDAC6 is the predominant cytoplasmic deacetylase in neurons suggests that GSK3beta dependent phosphorylation may enhance HDAC6 activity, resulting in a decrease in acetylation of tubulin and an inhibition of both mitochondrial motility and the transport of other kinesin-1 dependent cargoes. SIGNOR-278941 0.381 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 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-210079 0.665 WNT4 protein P56705 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-131832 0.649 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 0.2 ZBTB43 protein O43298 UNIPROT BDP1 protein A6H8Y1 UNIPROT unknown binding 9606 16542149 t miannu The zinc finger protein ZNF297B interacts with BDP1, a subunit of TFIIIB. Due to the essential role of BDP1 in Pol III transcription, we propose that ZNF297B may also regulate these transcriptional pathways. SIGNOR-225852 0.454 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT unknown phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 BTO:0000567 12445832 t gcesareni In this report we describe for the first time that c-Abl and Btk physically interact and that c-Abl can phosphorylate tyrosine 223 in the SH3 domain of Btk SIGNOR-245278 0.336 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t miannu JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein. SIGNOR-250081 0.339 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 10571231 t miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation SIGNOR-264108 0.2 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 0.2 LYN protein P07948 UNIPROT MCM7 protein P33993 UNIPROT up-regulates activity phosphorylation Tyr600 WASKDATyTSARTLL 9606 23764002 t miannu Lyn phosphorylates MCM7 at Y600.|These evidences suggest that Lyn mediated Y600 phosphorylation may regulate MCM7 function in DNA replication licensing. SIGNOR-278407 0.453 FOXL2 protein P58012 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2 SIGNOR-140391 0.7 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 0.521 FOXP3 protein Q9BZS1 UNIPROT CCL5 protein P13501 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 38339310 t miannu Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression SIGNOR-277727 0.434 ABL1 protein P00519 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000007;BTO:0000567 17254966 t gcesareni A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL SIGNOR-245293 0.595 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Ser21 KRTSSPRsPPSSSEI 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264775 0.2 GSK3B protein P49841 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates activity phosphorylation 9606 18675800 t miannu In T-cells, calcineurin de-phosphorylates NFATc1, leading to its nuclear import, while glycogen synthase kinase 3 beta (GSK3beta) phosphorylates NFATc1 and promotes its nuclear export.|We conclude that GSK3beta negatively regulates NFATc1 in vSMCs, and GSK3beta must be inactivated to allow NFAT activation during wound repair.Male Sprague-Dawley rats were obtained from Charles River (Montreal, PQ, Canada). SIGNOR-279185 0.588 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 0.295 AMP smallmolecule CHEBI:456215 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-265737 0.8 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 t lperfetto 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-209769 0.542 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270888 0.544 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser792 DKMRRASsYSSLNSL 10090 BTO:0002572 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. SIGNOR-161375 0.687 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264285 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL -1 15946941 t miannu  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.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. SIGNOR-276036 0.2 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 f The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines SIGNOR-253588 0.7 GSK3B protein P49841 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 20530674 t miannu Because GSK3\u03b2 phosphorylates Nmyc at T58, we assessed GSK3\u03b2 activation in Dex-treated MB cells. SIGNOR-279722 0.33 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys160 EAHQWFLkHEARPLA 9534 BTO:0000298 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. SIGNOR-270540 0.78 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT unknown phosphorylation Thr573 RQIRQGNtKQRIDEF -1 9456324 t lperfetto  A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. SIGNOR-248995 0.68 AKT proteinfamily SIGNOR-PF24 SIGNOR STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. SIGNOR-201121 0.2 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 0.727 LAMTOR3 protein Q9UHA4 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164775 0.932 BTG2 protein P78543 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254649 0.368 MAPK14 protein Q16539 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114079 0.592 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f gcesareni Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression. SIGNOR-254344 0.2 CDC14A protein Q9UNH5 UNIPROT KMT5A protein Q9NQR1 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. SIGNOR-248835 0.2 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 0.2 ARPC5 protein O15511 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251518 0.961 FANCM protein Q8IYD8 UNIPROT FANCF protein Q9NPI8 UNIPROT up-regulates binding 9606 20064461 t gcesareni Protein interaction motifs in fancm, designated mm1 and mm2, were identified. Mm1 interacts with the fa core complex by binding to fancf, whereas mm2 interacts with rm1 and topoisomerase iiialpha, components of the bs complex. SIGNOR-163101 0.932 Diprenorphine chemical CHEBI:4650 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258790 0.8 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 0.429 acyl-CoA smallmolecule CHEBI:17984 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-268106 0.8 CHEK1 protein O14757 UNIPROT TICRR protein Q7Z2Z1 UNIPROT down-regulates activity phosphorylation 9606 25557548 t miannu In principle, phosphorylation of Treslin by Chk1 may alter its conformation or directly affect its interactions with other proteins to preclude helicase activation.|The fact that the TRCT domain blocks the binding of Chk1 to Treslin suggests that Chk1 suppresses the initiating function of Treslin. SIGNOR-278924 0.432 CDKN1A protein P38936 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates binding 9606 19158493 t gcesareni P21-mediated degradation of cyclin b1 in response to dna damage is necessary for the maintenance of g2 cell cycle arrest. SIGNOR-183498 0.829 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 0.262 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr119 AGTAGALtPQHVRAH 9606 BTO:0001938 21364637 t miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells SIGNOR-277641 0.2 MAPK1 protein P28482 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr245 GFGTSPLtPSARISA -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274075 0.287 CD79B protein P40259 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000776 12324477 f gcesareni Bcr ligation resulted in p53 activation including its phosphorylation at ser15 SIGNOR-93526 0.308 Laminin-1 complex SIGNOR-C183 SIGNOR A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9361014 t lperfetto Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. SIGNOR-253255 0.547 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 0.328 L3MBTL2 protein Q969R5 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates activity binding 9606 31225475 t miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266786 0.2 NHLRC1 protein Q6VVB1 UNIPROT SLC1A2 protein P43004 UNIPROT up-regulates activity ubiquitination 9606 33368637 t miannu On the contrary, overexpression of the laforin/malin complex promotes the retention of GLT-1 at the plasma membrane.|This is due to a direct ubiquitination of GLT-1 by laforin and malin and/or to changes in the dynamics of its Nedd4.2-mediated endocytosis, which is assisted by specific adaptors (\u03b1- and \u03b2-arrestins). SIGNOR-278586 0.2 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR 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-258991 0.2 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Ala36 PESKATNaTLDPRSF -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263565 0.43 PRKCE protein Q02156 UNIPROT NLRP5 protein P59047 UNIPROT up-regulates activity phosphorylation Ser331 MQRKKESsVTEFISR 9606 BTO:0000007 19542546 t miannu MATER protein as substrate of PKCepsilon in human cumulus cells. we performed coimmunoprecipitation experiments using HEK293T cells expressing human MATER; a similar approach was then followed in human cumulus/follicular cells. In MATER(+)HEK293T cells, we observed that this protein acts as a phosphorylation substrate of PKCepsilon. Since PKCepsilon is known to collaborate with antiapoptotic signalling pathways, this suggests a novel mechanism for the function of MATER in follicular maturation. SIGNOR-263175 0.2 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 0.929 ETS1 protein P14921 UNIPROT CD8A protein P01732 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8413295 f miannu Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. SIGNOR-254078 0.256 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 0.8 XIAP protein P98170 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination -1 15749826 t lperfetto Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis. SIGNOR-134504 0.914 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 0.743 POLR2A protein P24928 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-266160 0.863 PRL protein P01236 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 10585417 t gcesareni Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor (prlr). SIGNOR-72810 0.924 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 t Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 0.46 CEP192 protein Q8TEP8 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 26012549 t miannu These findings demonstrated that Cep192 mediates the AurA-Plk1 interaction and that the formation of the Cep192-AurA-Plk1 complex could be important for activating AurA and Plk1. SIGNOR-266406 0.796 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HECTD3 protein Q5T447 UNIPROT up-regulates activity phosphorylation Thr157 ARLVPIDtPNHLQRQ 9606 BTO:0004461 28716524 t miannu HECTD3 binds and ubiquitinates caspase-9.Phosphorylation of HECTD3 by ERK is required for the association of HECTD3 and caspase-9. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK. SIGNOR-272330 0.2 AKT1 protein P31749 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-252505 0.435 USF2 protein Q15853 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 9731700 f miannu Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription. SIGNOR-255594 0.411 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000575 16469705 t gcesareni This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, SIGNOR-245310 0.654 PPM1A protein P35813 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16931515 t lpetrilli In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1. SIGNOR-149077 0.538 RAP1GDS1 protein P52306 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171418 0.485 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19185596 f miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. SIGNOR-260974 0.647 EIF2AK2 protein P19525 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 25360179 t miannu Silencing PKR gene expression in HepG2 cells with siRNA reduced STAT3 phosphorylation at Tyr705 and Ser727 (XREF_FIG).|The results also revealed that PKR activates STAT3, a transcription factor associated with primary liver tumors, which is suggested to promote tumor cell proliferation. SIGNOR-279612 0.612 Survival Factors stimulus SIGNOR-ST8 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity 19282669 f lperfetto Activation of receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) by growth factors or mitogens leads to the recruitment of an adaptor protein Grb2 (growth factor receptor bound protein) and the guanine nucleotide exchange factor (SOS). The SOS activates Ras to recruit and activate Raf at the plasma membrane by phosphorylation at multiple sites. MEK1/2 is which then phosphorylated at two serine residues that subsequently phosphorylates ERK1/2 on both threonine and tyrosine. Activated ERK1/2 phosphorylates RSK and both RSK and ERK translocate to the nucleus where they activates multiple transcription factors ultimately resulting in effector protein synthesis and causing changes in cell proliferation and survival. ERK phosphorylation of MEK and possibly Raf can inactivate the pathway at those steps creating a negative feedback loop. SIGNOR-250559 0.7 EFNA3 protein P52797 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells. SIGNOR-52312 0.804 POU5F1 protein Q01860 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254942 0.839 GSK3B protein P49841 UNIPROT FOXM1 protein Q08050 UNIPROT down-regulates quantity by destabilization phosphorylation Ser474 S-->A 9606 BTO:0002181 26912724 t miannu GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. SIGNOR-277208 0.355 KIF1C protein O43896 UNIPROT RAB6A protein P20340 UNIPROT up-regulates quantity relocalization -1 20360680 t miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. SIGNOR-266877 0.409 BRAF protein P15056 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates quantity by destabilization phosphorylation Thr88 ETSKYYVtIIDAPGH -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276405 0.262 OPHN1 protein O60890 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 t miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro SIGNOR-268399 0.591 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Ala369 DYAPVIPaNMDKKYR -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. SIGNOR-263635 0.366 LPAR5 protein Q9H1C0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257284 0.35 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1710 HVTSKCGsLKNIRHR -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-250165 0.418 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 0.535 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 0.379 SMARCC1 protein Q92922 UNIPROT SMARCE1 protein Q969G3 UNIPROT up-regulates quantity by stabilization 9606 20829358 f miannu We show that the mechanism of baf155-mediated stabilization of baf57 involves blocking its ubiquitination by preventing interaction with trip12, an e3 ubiquitin ligase. SIGNOR-167869 0.898 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser92 AAQMEVAsFLLSKEN 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250608 0.992 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR EDC3 protein Q96F86 UNIPROT down-regulates activity binding 10029 BTO:0000246 20051463 t miannu 14-3-3 binding to EDC3 resulted in a significant decrease in the binding of several key mRNA regulatory factors such as PABP and Y-box-binding protein 1 to EDC3. SIGNOR-262630 0.2 CID 132010322 chemical CID:132010322 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition 9606 31969702 t Luana ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 SIGNOR-261103 0.8 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270710 0.854 CABIN1 protein Q9Y6J0 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 9606 17172641 f gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. SIGNOR-151208 0.796 CAMK2B protein Q13554 UNIPROT RETREG1 protein Q9H6L5 UNIPROT up-regulates activity phosphorylation Ser151 AQLWRSLsESWEVIN -1 31930741 t miannu Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy.  SIGNOR-273554 0.2 MEAF6 protein Q9HAF1 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-269301 0.746 NMB protein P08949 UNIPROT NMBR protein P28336 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. SIGNOR-107022 0.767 MAPK14 protein Q16539 UNIPROT F3 protein P13726 UNIPROT down-regulates phosphorylation Ser290 GQSWKENsPLNVS 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. Our current study has identified p38_ as a major kinase, responsible for the phosphorylation of ser258 within the cytoplasmic domain of tf SIGNOR-199868 0.291 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 0.446 EDN1 protein P05305 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9767234 f miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252386 0.35 BCOR protein Q6W2J9 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 t miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-255276 0.547 PRKCA protein P17252 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity phosphorylation Ser896 SSFKRRRsSKDTSTG 10116 BTO:0000938 15936117 t miannu Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. SIGNOR-263177 0.417 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256381 0.2 RNF8 protein O76064 UNIPROT BCL10 protein O95999 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 24732096 t miannu Phosphorylated and ubiquitinated BCL10 is stabilized on the damage sites through binding to and presenting UBC13 to RNF168.|We thus concluded that BCL10 is ubiquitinated mainly with K63-linked ubiquitination by RNF8. SIGNOR-278778 0.328 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ -1 15946941 t done miannu PKA Phosphorylates GRK1 on Ser21. Phosphorylation by PKA inhibits GRK1 activity. SIGNOR-274079 0.2 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 0.8 bisphenol A chemical CHEBI:33216 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9751507 t miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings.  SIGNOR-268739 0.8 PRKCD protein Q05655 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Thr790 TRNDVAPtLMSVPRY 10029 27203386 t Manara Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin. SIGNOR-260893 0.2 CEBPD protein P49716 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 f CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. SIGNOR-254060 0.272 CSNK2A1 protein P68400 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Ser267 PPTTSSDsEEEQEDE 9606 BTO:0000007 22025562 t miannu  Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. SIGNOR-276388 0.504 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 0.962 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY2 protein P41231 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-257563 0.8 ZMIZ1 protein Q9ULJ6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 10090 BTO:0001825 26522984 t miannu The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions SIGNOR-263936 0.452 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser273 RPASVNGsPSATSES 9606 BTO:0000007 16446428 t gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 SIGNOR-249580 0.654 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling. SIGNOR-37154 0.529 SIAH1 protein Q8IUQ4 UNIPROT YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization ubiquitination Lys304 PQDGKETkAADPPAE 9606 35273154 t miannu Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain.|SIAH1 ubiquitinated YBX-1 at its K304 through the RING domain. SIGNOR-278780 0.244 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2A protein Q9BTU6 UNIPROT down-regulates activity chemical inhibition -1 21704602 t Luana Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity SIGNOR-258317 0.8 MARK3 protein P27448 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9534 9543386 t miannu C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function. SIGNOR-250176 0.485 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2116 VGRGLQLtPGIGGMQ 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181018 0.374 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 0.37 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A9 protein P06702 UNIPROT up-regulates activity chemical activation 9606 BTO:0001044 16690079 t miannu S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization. SIGNOR-261934 0.8 MAML2 protein Q8IZL2 UNIPROT NOTCH1 protein P46531 UNIPROT 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-94065 0.839 NFKBIE protein O00221 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates binding 9606 BTO:0001271 SIGNOR-C13 12835716 t gcesareni Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe SIGNOR-102774 0.541 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 0.449 (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 0.8 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser328 GQAGSTIsNSHAQPF 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-249330 0.6 WARS1 protein P23381 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI down-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270510 0.8 PAK1 protein Q13153 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation 9606 25860930 t miannu It has been shown that PAK1 phosphorylates and activates MLC2, leading to cell motility [ xref ]. SIGNOR-280053 0.484 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR PTPN1 protein P18031 UNIPROT up-regulates activity binding 16115959 t lperfetto N this study, we demonstrate an essential role for protein-tyrosine phosphatase (PTP)-1B in this process. In resting platelets, c-Src forms a complex with alphaIIbbeta3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to alphaIIbbeta3 triggers PTP-1B recruitment to the alphaIIbbeta3-c-Src-Csk complex in a manner that is dependent on c-Src and specific tyrosine (tyrosine 152 and 153) and proline (proline 309 and 310) residues in PTP-1B. Studies of PTP-1B-deficient mouse platelets indicate that PTP-1B is required for fibrinogen-dependent Csk dissociation from alphaIIbbeta3, dephosphorylation of c-Src tyrosine 529, and c-Src activation. SIGNOR-261800 0.481 C1RL protein Q9NZP8 UNIPROT HP protein P00738 UNIPROT up-regulates activity cleavage Arg161 NPANPVQrILGGHLD 9534 BTO:0001538 15385675 t miannu We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction. SIGNOR-256358 0.375 aldosterone smallmolecule CHEBI:27584 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-258712 0.8 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 0.7 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 0.492 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser354 VSLKPLHsVNNPILR 9606 BTO:0000007 35064619 t miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. SIGNOR-276746 0.2 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.929 17beta-estradiol smallmolecule CHEBI:16469 ChEBI 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI up-regulates quantity precursor of 9606 BTO:0000093 8790407 t Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. SIGNOR-269753 0.8 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 19934023 t gcesareni We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657. SIGNOR-161824 0.309 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 0.523 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192904 0.8 ATM protein Q13315 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser239 DPMTQDGsQPMDTNM 9606 22588298 t llicata On genotoxic stress, atm phosphorylates bmps-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase ppm1a, leading to enhanced activation and upregulation of smad1. SIGNOR-197533 0.2 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activitywe have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. SIGNOR-152958 0.57 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120240 0.316 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 0.2 HSPA5 protein P11021 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 28286085 f lperfetto The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. SIGNOR-265283 0.7 MECP2 protein P51608 UNIPROT RBFOX1 protein Q9NWB1 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-264681 0.28 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 9793625 t Mometasone furoate (MF, CAS 83919-23-7, Sch 32088), budesonide (BUD, CAS 51372-29-3), fluticasone propionate (FP, CAS 80474-14-2), and triamcinolone acetonide (TA, CAS-76-25-5) are corticosteroids. All of the test compounds had a higher affinity for the recombinant glucocorticoid receptor than the reference glucocorticoid receptor ligand, dexamethasone (DEX, CAS 50-02-2). All compounds showed greater potency than dexamethasone in stimulating transcription of a synthetic target gene regulated by a glucocorticoid response element. SIGNOR-253053 0.8 PCSK7 protein Q16549 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates phosphorylation 9606 11259586 t gcesareni This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation SIGNOR-105783 0.2 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr500 TSLGSQSyEDMRGIL 10090 BTO:0000776 10933394 t lperfetto Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni SIGNOR-249376 0.772 CDK5 protein Q00535 UNIPROT ADD1 protein P35611 UNIPROT up-regulates activity phosphorylation Thr724 KKKKKFRtPSFLKKS 9606 BTO:0000815 31548578 t miannu We found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells. SIGNOR-277487 0.255 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 22640926 f fspada We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis. SIGNOR-197634 0.7 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr315 MPMDTSVyESPYSDP 9606 BTO:0000661 11828374 t lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. SIGNOR-247048 0.2 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 0.312 NCOR2 protein Q9Y618 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 11331609 t gcesareni Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt SIGNOR-107260 0.467 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250084 0.525 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 0.753 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 0.7 ZBTB16 protein Q05516 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-72377 0.361 IRF2BPL protein Q9H1B7 UNIPROT GNRH1 protein P01148 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 17627301 t miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. SIGNOR-267154 0.416 SIRT1 protein Q96EB6 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity deacetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310. SIGNOR-238817 0.722 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 23263282 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-200206 0.2 PJA1 protein Q8NG27 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 9606 32127355 t miannu In summary, these results indicated that PJA1 promotes the ubiquitination of phosphorylated SMAD3, resulting in reduced activity of a TGF-\u03b2/SMAD3/\u03b22SP-dependent tumor-suppressing pathway in HCC cells ( xref ). SIGNOR-278832 0.391 ETS1 protein P14921 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20392592 f miannu High ETS1 expression levels in all resistant MCF-7 sublines may lead to the upregulation of the transcription of MDR1 gene. SIGNOR-254077 0.2 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B SIGNOR-248437 0.743 ARHGEF7 protein Q14155 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 f gcesareni We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1. SIGNOR-155744 0.637 SND1 protein Q7KZF4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30365124 f irozzo SND1 upregulation is a common phenomenon in different human malignant tissues. We found that SND1 overexpression significantly promoted cell proliferation and tumor growth in vitro and in vivo. SIGNOR-259135 0.7 FLT1 protein P17948 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277231 0.257 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQA1 protein P01909 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-253991 0.285 PI4K2B protein Q8TCG2 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269102 0.8 SEMA7A protein O75326 UNIPROT PLXNC1 protein O60486 UNIPROT up-regulates binding 9606 10520995 t gcesareni Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. SIGNOR-71260 0.913 TNFRSF17 protein Q02223 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79504 0.265 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 0.706 SETD2 protein Q9BYW2 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates activity methylation Lys40 DGQMPSDkTIGGGDD 9606 BTO:0000007 27518565 t Gianni The histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy SIGNOR-269090 0.244 TG101209 chemical CHEBI:90304 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207263 0.8 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 0.7 IMP smallmolecule CHEBI:17202 ChEBI GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity precursor of 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-268130 0.8 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 0.675 MTARC1 protein Q5VT66 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 24500710 t miannu our results indicate that mARC can generate nitric oxide (NO) from nitrite when forming an electron transfer chain with NADH, cytochrome b5, and NADH-dependent cytochrome b5 reductase. expression of mARC-1 in HEK cells using a lentivirus vector was used to confirm cellular nitrite reduction to NO. SIGNOR-261419 0.8 VIP protein P01282 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 t gcesareni Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip). SIGNOR-116122 0.864 EFNA1 protein P20827 UNIPROT EPHA4 protein P54764 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-56907 0.823 quinpirole chemical CHEBI:75401 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. SIGNOR-258441 0.8 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr338 VPVKSRKtTLEQPPS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276775 0.643 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19763573 f miannu PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB. SIGNOR-254654 0.261 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 0.8 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser472 TQREGVSsLDSSSLS 9606 10893229 t gcesareni In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3. SIGNOR-79143 0.687 CCNC protein P24863 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-130589 0.2 RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 17350185 t Luana The IL-6 promoter was stimulated by NF-kB RelA protein.  SIGNOR-266088 0.692 NTN1 protein O95631 UNIPROT 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-268376 0.734 EGFR protein P00533 UNIPROT KRT14 protein P02533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11875647 f Regulation of expression miannu UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK. SIGNOR-251901 0.458 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 0.634 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186943 0.2 AKAP12 protein Q02952 UNIPROT PRKCA protein P17252 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-271836 0.459 PDX1 protein P52945 UNIPROT NKX6-1 protein P78426 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-255542 0.503 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation 9606 25026293 t miannu All of these results lead to the conclusion that PPM1A inhibits the TGF-\u03b2-induced the activity of Smad2, Smad3 and transcriotional responses, whereas depletion of PPM1A enhances the activation of TGF-\u03b2/Smads signaling in bladder cancer cells.|Protein phosphatase PPM1A has been reported to dephosphorylate TGF-\u03b2-activated Smad2/3, thus inhibiting the TGF-\u03b2 signaling pathway. SIGNOR-277034 0.668 XRCC5 protein P13010 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002284 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-225537 0.307 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1404 GREEFYStHPHFMTQ 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. SIGNOR-188433 0.2 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 0.532 UVRAG protein Q9P2Y5 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260322 0.821 LNX2 protein Q8N448 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32714586 t miannu Notably LNX2 knockdown caused an increase in NUMB levels and decreased levels of the NOTCH2 intracellular domain , as well as decreased expression of the NOTCH target gene Hes1 .|They also showed for the first time that LNX2 could indeed ubiquitinate NUMB, something that had previously only been shown for LNX1. SIGNOR-278818 0.605 ERBB2 protein P04626 UNIPROT BBC3 protein Q96PG8 UNIPROT down-regulates activity phosphorylation 9606 24236056 t miannu These results show for the first time that PUMA can be phosphorylated at tyrosine residues directly by HER2.|Together, our results demonstrate, for the first time, that PUMA can be tyrosine phosphorylated and that HER2-mediated phosphorylation destabilizes PUMA protein. SIGNOR-278224 0.281 CBLB protein Q13191 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24885194 t miannu The ubiquitin ligase Cbl-b also ubiquitinated and degraded IGF-IR and inhibited the Akt/ERK-miR-200c-ZEB2 axis, leading to the repression of IGF-I-induced EMT. SIGNOR-278607 0.422 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 t inferred from 70% family members lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-270103 0.2 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191406 0.8 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 0.7 SMCR8 protein Q8TEV9 UNIPROT WIPI2 protein Q9Y4P8 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000007 28169830 t Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2 SIGNOR-252028 0.271 GSK3B protein P49841 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Thr180 KDDFQRLtPSYNADI 9606 BTO:0001033 32871104 t miannu Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. SIGNOR-277528 0.2 DYRK1A protein Q13627 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-183680 0.305 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 0.8 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 0.299 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236471 0.2 26S Proteasome complex SIGNOR-C307 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity destabilization 10090 BTO:0003569 9233789 t Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. SIGNOR-270340 0.416 MED28 protein Q9H204 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-266674 0.839 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15207708 f gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. SIGNOR-236845 0.757 lenalidomide chemical CHEBI:63791 ChEBI CSNK1A1 protein P48729 UNIPROT down-regulates quantity by destabilization 9606 BTO:0000670 26131937 f gcesareni We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN) SIGNOR-236895 0.8 MAPK1 protein P28482 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-262958 0.534 NEK3 protein P51956 UNIPROT NEK3 protein P51956 UNIPROT down-regulates activity phosphorylation Thr165 FACTYVGtPYYVPPE -1 27489110 t Manara Autophosphorylation at Thr-165 is required for NEK3 kinase activity in vitro. SIGNOR-260919 0.2 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr458 CKTPSSNtLDDYMSC -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276222 0.381 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-252868 0.765 RDH5 protein Q92781 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265114 0.8 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 0.8 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 0.313 CAPZA1 protein P52907 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto Finally, the capZ protein recaps the barbed filament ends to complete the assembly and these actin cytoskeletons can be used for cellular contraction, resulting in the final activated platelet shape SIGNOR-261855 0.7 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 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-161706 0.746 ACVR2B protein Q13705 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 21966641 t areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254984 0.776 FOXO1 protein Q12778 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 16308421 f gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. SIGNOR-142150 0.581 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr604 YKVRIDEyDYSKPIQ -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-262873 0.2 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 0.354 CDKN2AIP protein Q9NXV6 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 16803988 t miannu In the nucleoplasm, carf interacts with p53 and enhances its function. SIGNOR-147360 0.382 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244377 0.2 SMC5/6 complex SIGNOR-C374 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 27427983 f miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265488 0.7 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18971376 f miannu HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. SIGNOR-254222 0.37 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 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-268602 0.248 APOBEC3G protein Q9HC16 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-261329 0.7 ADSS1 protein Q8N142 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-267350 0.8 SIN3A protein Q96ST3 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 16254079 t Chromatin immunoprecipitation (ChIP) and DNA affinity precipitation analysis demonstrated that Ebp1 and Sin3A associate at the PSA and E2F1 promoters. Functionally, Sin3A enhanced the ability of Ebp1 to repress transcription of androgen receptor (AR) and E2F1 regulated genes. SIGNOR-253663 0.2 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 0.717 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251239 0.686 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267597 0.546 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 0.404 VAV1 protein P15498 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260580 0.75 CASP6 protein P55212 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261753 0.372 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr216 VLNSHDLyQKVAQEI 9606 15952790 t llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. SIGNOR-138146 0.606 TGFB1 protein P01137 UNIPROT CCNA2 protein P20248 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 7592630 f gcesareni Expression of one of these components, cyclin a, is inhibited by tgf-beta treatment. We have identified a 760-base pair fragment of the human cyclin a gene promoter that is sufficient to confer tgf-beta responsiveness. SIGNOR-29516 0.285 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-141416 0.2 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 22505454 t gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. SIGNOR-196961 0.364 ARNT protein P27540 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR form complex binding 9606 27692180 t miannu HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life SIGNOR-267448 0.787 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys206 DLINLAKkRTNIIPV 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275893 0.271 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 0.447 ketotifen chemical CHEBI:92511 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-257789 0.8 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 0.296 H2AC4 protein P04908 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263874 0.2 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 0.8 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 0.2 ROCK1 protein Q13464 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10652353 t lperfetto Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop. SIGNOR-74569 0.617 S100A9 protein P06702 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004730 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-261932 0.7 CDK1 protein P06493 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates activity phosphorylation Thr346 LEEGVHLtPFRQKVS 9606 24055156 t lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. SIGNOR-265263 0.2 MAP3K3 protein Q99759 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000298 9162092 t lperfetto These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3. SIGNOR-48625 0.558 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 0.2 MAPK1 protein P28482 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser454 PSPAPGGs -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277361 0.474 ACADL protein P28330 UNIPROT myristoyl-CoA(4-) smallmolecule CHEBI:57385 ChEBI down-regulates quantity chemical modification 9606 18227065 t miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. SIGNOR-280326 0.8 CHEK1 protein O14757 UNIPROT WEE1 protein P30291 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni Chk1 also phosphorylates and stabilizes wee1. SIGNOR-163164 0.611 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxotetradecanoyl-CoA smallmolecule CHEBI:28726 ChEBI up-regulates quantity chemical modification 9606 29551309 t miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex SIGNOR-280336 0.8 LRFN4 protein Q6PJG9 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 t miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. One possibility is that SALM3, which is capable of inducing presynaptic differentiation in contacting axons [19], recruits PSD-95 or SAP102 to the sites of early synaptic adhesion. SIGNOR-264096 0.682 LAMTOR complex SIGNOR-C26 SIGNOR RAGAC complex SIGNOR-C113 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids. SIGNOR-228155 0.879 PRKDC protein P78527 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity phosphorylation Ser1987 GSQSTTIsSLSEKSK 9606 32832608 t miannu It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 / T373 and T1985 / S1987 / S1988 sites .|It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 and T373 and T1985/S1987/S1988 sites. SIGNOR-278324 0.702 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 0.805 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10230394 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-67387 0.542 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxotetradecanoyl-CoA smallmolecule CHEBI:28726 ChEBI down-regulates quantity chemical modification 9606 29551309 t miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex SIGNOR-280338 0.8 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 0.891 MAPK10 protein P53779 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. SIGNOR-166690 0.301 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser330 ASTGKSKsPCQTLGG 9606 23977114 t lperfetto Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined SIGNOR-202536 0.343 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT MT-ND4L protein P03901 UNIPROT down-regulates activity binding 9606 BTO:0000764 16157265 t lperfetto This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication. SIGNOR-260253 0.2 DNA_damage stimulus SIGNOR-ST1 SIGNOR CDKN2A protein Q8N726 UNIPROT up-regulates activity 9606 25101116 f lperfetto ARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis. Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. SIGNOR-245493 0.7 DLL4 protein Q9NR61 UNIPROT NRP1 protein O14786 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18339870 f gcesareni Dll4 down-regulates vascular endothelial growth factor (vegf)_ receptor_ 2 and nrp1 expression and inhibits vegf function SIGNOR-178029 0.361 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 0.383 CSK protein P41240 UNIPROT FGR protein P09769 UNIPROT down-regulates activity phosphorylation Tyr523 FTSAEPQyQPGDQT -1 7515063 t llicata CSK catalyzed phosphorylation affects Tyr-511 of c-Fgr, homologous to Tyr-527 of c-Src and it prevents the autophosphorylation normally occurring at c-Fgr Tyr-400, homologous to c-Src Tyr-416. | Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation. SIGNOR-250779 0.537 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0001332 19903340 f lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression SIGNOR-189105 0.634 TAF9 protein Q16594 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-263920 0.621 MAPK8 protein P45983 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates activity phosphorylation 9606 10075927 t miannu JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1 SIGNOR-279218 0.277 RAP1A protein P62834 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0003104 12808052 t lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. SIGNOR-253362 0.482 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr448 GDDSDEDyEKVPLPN 9534 BTO:0004055 12709437 t lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk. SIGNOR-246596 0.552 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194566 0.8 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 0.281 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 0.784 FN1/SDC4 complex SIGNOR-C210 SIGNOR WNT7A protein O00755 UNIPROT up-regulates 23290138 t apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells SIGNOR-255287 0.312 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 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-37545 0.403 EFNA2 protein O43921 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 10072375 t tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) SIGNOR-65413 0.816 LIMK1 protein P53667 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 9655398 t lperfetto Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo SIGNOR-58596 0.703 LHX2 protein P50458 UNIPROT MSX1 protein P28360 UNIPROT down-regulates activity binding -1 9697309 t 2 miannu Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity SIGNOR-241327 0.477 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 0.3 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 0.423 PRKACG protein P22612 UNIPROT PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267415 0.325 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 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-262911 0.318 MIB2 protein Q96AX9 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates quantity ubiquitination 9606 20604708 t miannu Mib2 is localized to the PSD of dendrites in hippocampal neurons and directly ubiquitinates GluN2B in a manner dependent on the non receptor tyrosine kinase Fyn.|These findings suggest that Mib2 mediates proteasome dependent degradation of GluN2B subunits, which may provide a reciprocal mechanism to SCF Fbx2 regulation of GluN2A. SIGNOR-278762 0.366 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT RPS3 protein P23396 UNIPROT down-regulates activity binding -1 33188728 t miannu Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. SIGNOR-262507 0.2 Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 24311584 f miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. SIGNOR-263713 0.7 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 0.7 SLBP protein Q14493 UNIPROT H3Y1 protein P0DPK2 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-265419 0.2 EIF1B protein O60739 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 14600024 f lperfetto Binding of eIF1 to the 40S subunit would block access of the 60S SIGNOR-269146 0.251 PIGF protein Q07326 UNIPROT PIGO protein Q8TEQ8 UNIPROT down-regulates quantity by destabilization 10029 BTO:0000246 15632136 f 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-261360 0.71 LFNG protein Q8NES3 UNIPROT JAG1 protein P78504 UNIPROT down-regulates binding 9606 BTO:0000007 15574878 t gcesareni Although jagged1-induced signaling was suppressed by lfng and mfng SIGNOR-131560 0.486 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 0.537 RIPK2 protein O43353 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 10559258 t miannu RIP2 directly phosphorylates and activates ERK2 in vivo and in vitro. SIGNOR-279106 0.295 PKA proteinfamily SIGNOR-PF17 SIGNOR RAP1A protein P62834 UNIPROT up-regulates activity phosphorylation Ser180 KKKPKKKsCLLL 9606 BTO:0000751 17068197 t Marta Tosoni Rap1 is phosphorylated and activated by PKA in neutrophils and platelets SIGNOR-278057 0.2 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 0.7 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0001938 11463392 t lperfetto Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release SIGNOR-109506 0.663 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 0.2 gamma-secretase complex SIGNOR-C98 SIGNOR DSCAM protein O60469 UNIPROT down-regulates quantity cleavage 9606 BTO:0000938 30745319 t miannu γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival. SIGNOR-264271 0.2 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 0.8 CCL2 protein P13500 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32446778 f Luana In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNŒ±, IFNŒ≥, IL-1Œ≤, IL-6, IL-12, IL-18, IL-33,TNFŒ±, TGFŒ≤) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatory response. SIGNOR-261317 0.7 LETM1 protein O95202 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected. SIGNOR-262546 0.287 ropinirole chemical CHEBI:8888 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 9057850 t miannu Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively) SIGNOR-258600 0.8 PLRG1 protein O43660 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-239444 0.747 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 0.475 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 0.905 TWIST1 protein Q15672 UNIPROT NR2F1 protein P10589 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-255531 0.25 AVPR1B protein P47901 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257063 0.267 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001023 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255614 0.383 JAK2 protein O60674 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249493 0.707 STUB1 protein Q9UNE7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24578159 t miannu CHIP promotes TRAF6 ubiquitination and degradation.|These results suggest that CHIP negatively regulates the stability of TRAF6. SIGNOR-278670 0.466 A6/b1 integrin complex SIGNOR-C164 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253282 0.378 ZMYND8 protein Q9ULU4 UNIPROT MMP1 protein P03956 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262042 0.2 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 14699166 t llicata Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells. SIGNOR-120492 0.527 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 0.726 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 20974802 f 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-168992 0.391 MC4R protein P32245 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268707 0.521 PTPN14 protein Q15678 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity dephosphorylation 9606 32152405 t miannu Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo.|Moreover, the CAV1 (Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine 14, as well as suppressed CAV1 enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29 (US)] and breast cancer (MDA-MB-231) cell lines. SIGNOR-277054 0.2 PPP2CA protein P67775 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-248620 0.446 WNT5B protein Q9H1J7 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131888 0.625 SRC protein P12931 UNIPROT SLC11A1 protein P49279 UNIPROT up-regulates activity phosphorylation Tyr15 QRLSGSSyGSISSPT 9606 29723216 t miannu In this study, we provide evidence that SLC11A1 is phosphorylated by Src family kinases at tyrosine 15 present in a conserved tyrosine-based motif (YGSI) among all species. SIGNOR-278500 0.281 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 0.592 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr904 SLRLVMEyLPSGCLR 9606 18250158 t lperfetto Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro SIGNOR-160664 0.2 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-123656 0.317 PLK1 protein P53350 UNIPROT CLASP2 protein O75122 UNIPROT up-regulates activity phosphorylation Ser1234 QGYDNSEsSVRKACV 9606 23045552 t miannu Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore-microtubule attachments.|Finally, we demonstrate that CLASP2 phosphorylation on S1234 and S1255 by Cdk1 and Plk1, respectively, increases with conditions that allow the establishment and stabilization of KT\u2013MT attachments ( xref ). SIGNOR-278321 0.622 YAP1 protein P46937 UNIPROT KIF23 protein Q02241 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276567 0.2 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 0.882 PRKCE protein Q02156 UNIPROT GLS protein O94925 UNIPROT up-regulates activity phosphorylation Ser314 RYVGKEPsGLRFNKL 9606 BTO:0002552 29515166 t miannu PKCε is the kinase that phosphorylates GAC at Ser314. SIGNOR-277387 0.2 IKBKE protein Q14164 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 19481526 t miannu CYLD is phosphorylated by IKK\u03b5 at Ser418.|Together, these observations demonstrate that I\u03baB kinase\u03b5-mediated phosphorylation of CYLD at Ser418 inhibits CYLD deubiquitinase activity. SIGNOR-278311 0.441 PAFAH1B1 protein P43034 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 20133715 f miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. SIGNOR-252169 0.7 TNFRSF1A protein P19438 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization 10090 BTO:0002572;BTO:0000801 21232017 f lperfetto Tnfr1-induced phosforylation and degradarionn of ikb are almost completely abolished in tradd-deficient mefs,these hallmarks of classical nf-kn signaling are only attenuated in tradd-deficient macrophage. SIGNOR-235789 0.557 PAK1 protein Q13153 UNIPROT AJUBA protein Q96IF1 UNIPROT up-regulates activity phosphorylation 9606 22105346 t miannu The Rac effector PAK1 was also transiently activated upon cell-cell adhesion and directly phosphorylated Ajuba (Thr172). SIGNOR-278449 0.256 AKT2 protein P31751 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-249582 0.292 NR0B2 protein Q15466 UNIPROT NR1H3 protein Q13133 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-91996 0.477 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 0.2 SMAD7 protein O15105 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0001130 15684397 f gcesareni In the current study, our data indicate that both smad7 and p38 map kinase positively contributed to the accumulation of -catenin SIGNOR-133447 0.7 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser285 QRVPSYDsFDSEDYP 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-250687 0.309 CTNNB1 protein P35222 UNIPROT TCF7 protein P36402 UNIPROT up-regulates binding 9606 BTO:0000782 15735151 t 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-134282 0.759 LRFN5 protein Q96NI6 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity binding 9606 BTO:0000938 27225731 t miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). SIGNOR-264087 0.351 pemetrexed disodium chemical CHEBI:63722 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 t miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). SIGNOR-259290 0.8 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 0.401 RIOK3 protein O14730 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates activity phosphorylation Ser828 GRARADEsTYVLVAH 9606 BTO:0000007 25865883 t lperfetto RIOK3 mediates phosphorylation of MDA5 Ser-828|RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response SIGNOR-264576 0.468 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 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1166 SDDFKRDsVSGGGPC 9606 BTO:0000007 24431445 t miannu Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. SIGNOR-276617 0.2 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 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-140085 0.458 LNX1 protein Q8TBB1 UNIPROT ABCA1 protein O95477 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-272902 0.242 [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 0.8 PTK2B protein Q14289 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-262876 0.71 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 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-269492 0.8 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 0.321 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275952 0.2 TBX5 protein Q99593 UNIPROT MTSS1 protein O43312 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255254 0.25 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 0.8 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 0.339 AGTR1 protein P30556 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257017 0.643 RFX5 protein P48382 UNIPROT RFX complex complex SIGNOR-C104 SIGNOR form complex binding -1 10825209 t miannu RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes SIGNOR-221565 0.892 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation 9606 15951562 t gcesareni Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases. SIGNOR-138080 0.569 HES1 protein Q14469 UNIPROT CTNND2 protein Q9UQB3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001033 21106062 f miannu Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression. SIGNOR-251877 0.346 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr853 PREKRRStGVSFWTQ 10090 10601309 t lperfetto Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850). SIGNOR-249034 0.774 CDC25A protein P30304 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 t lperfetto Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A SIGNOR-245452 0.746 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 0.362 CKM complex complex SIGNOR-C406 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates activity 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-273149 0.362 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L6 protein O14933 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271319 0.648 SDC3 protein O75056 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 10090 BTO:0002314 20696709 t gcesareni Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. SIGNOR-244072 0.379 ARAP1 protein Q96P48 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260452 0.531 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 0.825 PRKACA protein P17612 UNIPROT KCNJ3 protein P48549 UNIPROT unknown phosphorylation Ser385 NSKERHNsVECLDGL 9606 19151997 t llicata Using this approach, we identified s385 as an in vitro phosphorylation site. Mutation of this residue to alanine resulted in a reduced sensitivity of kir3.1* currents to h89 and forskolin, confirming an in vivo role for this novel site of the kir3.1 channel subunit in its regulation by pka. SIGNOR-183475 0.343 GPIb-IX-V complex complex SIGNOR-C270 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 32644488 f lperfetto Therefore, VWF cannot bind to the GpIb receptors on platelets via the A1 domain to induce platelet aggregation and further hemostasis.  SIGNOR-261866 0.7 AKT1 protein P31749 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 t miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. SIGNOR-277237 0.465 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-252921 0.2 EP300 protein Q09472 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 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-255025 0.687 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 0.2 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser393 NLQIRETsLDTKSVS -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-250629 0.427 PRKCB protein P05771 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. SIGNOR-248914 0.361 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 0.904 GSK3B protein P49841 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-198142 0.272 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 0.64 Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273454 0.7 GSK3B protein P49841 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-60655 0.739 RFX3 protein P48380 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 32725242 f miannu RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process. SIGNOR-266927 0.7 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 22452896 t Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. gcesareni Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors. SIGNOR-196760 0.8 7alpha,25-dihydroxycholesterol smallmolecule CHEBI:37623 ChEBI GPR183 protein P32249 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-257504 0.8 ELOVL1 protein Q9BW60 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267896 0.8 PRKCA protein P17252 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-128714 0.258 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 0.294 CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44557 0.871 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity precursor of 9606 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267261 0.8 sildenafil chemical CHEBI:9139 ChEBI PDE5A protein O76074 UNIPROT down-regulates activity chemical inhibition -1 10385692 t Luana Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. SIGNOR-258343 0.8 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 0.249 CDK4 protein P11802 UNIPROT PAX3 protein P23760 UNIPROT up-regulates activity phosphorylation Ser430 TTVSASCsQRLDHMK 9606 23469153 t miannu In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro . SIGNOR-278512 0.296 AKT3 protein Q9Y243 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t gcesareni When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. SIGNOR-62257 0.496 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits SIGNOR-254963 0.61 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. SIGNOR-88748 0.34 CLCF1 protein Q9UBD9 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-6 SIGNOR-47959 0.56 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000568 16890161 t gcesareni Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin. SIGNOR-148671 0.79 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 0.317 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271339 0.602 HMGB1 protein P09429 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 10090 25014009 t gcesareni HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs) SIGNOR-252059 0.803 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 20150555 t lperfetto 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-216940 0.414 calcium(2+) smallmolecule CHEBI:29108 ChEBI GSN protein P06396 UNIPROT up-regulates activity chemical activation 9606 BTO:0000132 27871158 t lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. SIGNOR-261844 0.8 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser269 SEEGQELsDEDDEVY 9606 12167711 t gcesareni Hypophosphorylation of mdm2 augments p53 stability. SIGNOR-91191 0.345 AR protein P10275 UNIPROT AKR1C3 protein P42330 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 22971343 f miannu Both AR antagonism and androgen deprivation can upregulate AKR1C3. SIGNOR-253737 0.448 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 0.298 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCD protein Q05655 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190350 0.8 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 12781173 t Luana Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. SIGNOR-257896 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-66032 0.2 LTK protein P29376 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells. SIGNOR-49531 0.314 BRCA1 protein P38398 UNIPROT NSD2 protein O96028 UNIPROT down-regulates quantity by destabilization ubiquitination Lys292 EGEGQFEkLCQESAK 9606 32826945 t miannu Proteomic data analysis revealed interaction between NSD2 and BRCA1 and further study revealed that BRCA1 ubiquitinates NSD2 at K292 residue.|These results suggested that BRCA1 interacts with and promotes degradation of NSD2 via polyubiquitination . SIGNOR-278745 0.2 THRA protein P10827 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 t scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. SIGNOR-267257 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248373 0.614 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol chemical CHEBI:111176 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258724 0.8 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 0.879 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 0.414 HSP90AA1 protein P07900 UNIPROT CBLL1 protein Q75N03 UNIPROT up-regulates quantity binding 9606 BTO:0000007 31952268 t miannu By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. SIGNOR-271474 0.2 E2F1 protein Q01094 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity 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-253864 0.7 CSNK2A1 protein P68400 UNIPROT CREB3 protein O43889 UNIPROT down-regulates quantity by destabilization phosphorylation Ser46 LPLSEVPsDWEVDDL -1 31941600 t miannu Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3. SIGNOR-277501 0.2 FZD9 protein O00144 UNIPROT SPRY4 protein Q9C004 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15705594 f miannu In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity. SIGNOR-253035 0.281 CAMKK2 protein Q96RR4 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates activity phosphorylation Thr200 EHQVLMKtVCGTPGY 7615569 t llicata Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation. SIGNOR-250718 0.62 CD19 protein P15391 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity binding 10090 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-242897 0.724 PCSK5 protein Q92824 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270334 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 t miannu Here, we show that protein kinase A (PKA) phosphorylates the PP2Cβ, which was inhibited by PKA-specific inhibitor, H89. Mutation analysis of serine residues in PP2Cβ revealed that Ser-195 in PP2Cβ is phosphorylated by PKA. Importantly, PKA inhibition by H89 abrogated the Forskolin-induced destabilization of PP2Cβ against ubiquitin-dependent proteosomal degradation pathway. SIGNOR-276494 0.2 LPAR1 protein Q92633 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-257091 0.544 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCND3 protein P30281 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189975 0.8 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 0.42 MYCT1 protein Q8N699 UNIPROT BCL2 protein P10415 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-261735 0.2 NDUFS3 protein O75489 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262177 0.87 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT up-regulates activity binding 10090 19106114 t miannu EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. SIGNOR-254918 0.442 SNAP23 protein O00161 UNIPROT STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  SIGNOR-261895 0.731 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 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RBBP8 protein Q99708 UNIPROT up-regulates activity phosphorylation Ser327 ELPTRVSsPVFGATS 9606 BTO:0000567 15485915 t lperfetto Ser327 site is a Ser-Pro site, a preferred phosphorylation site by cyclin-dependent kinases|Unlike wild-type CtIP, the S327A mutant did not bind to BRCA1 BRCT domains in vitro (Fig. ​(Fig.1C)1C) and failed to associate with BRCA1 in vivo (Fig. ​(Fig.1D),1D), suggesting that residue Ser327 of CtIP is critical for the CtIP-BRCA1 interaction. SIGNOR-263227 0.565 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 0.588 AXIN2 protein Q9Y2T1 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t lperfetto 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-228003 0.741 STXBP2 protein Q15833 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-267727 0.543 PIGBOS1 protein A0A0B4J2F0 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31653868 f miannu We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels SIGNOR-261041 0.2 ARNT protein P27540 UNIPROT CA9 protein Q16790 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22387692 f lperfetto The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. SIGNOR-253706 0.524 ARID5B protein Q14865 UNIPROT PHF2 protein O75151 UNIPROT up-regulates activity binding 9606 BTO:0000007 21532585 t miannu We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity. SIGNOR-264515 0.56 TBX21 protein Q9UL17 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 t In turn, T-bet is an IFN-gamma activator (Szabo et al., 2000), thus creating an indirect positive feedback. Furthermore, it has been shown that ectopic T-bet is able to induce the transcription of its own gene SIGNOR-254294 0.2 CDK5 protein Q00535 UNIPROT FOXC2 protein Q99958 UNIPROT up-regulates activity phosphorylation 9606 26327394 t miannu Cdk5 phosphorylates Foxc2 and activates Foxc2 dependent transcription. SIGNOR-279156 0.35 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Ser893 PRYHKRTsSAVWNSP 9606 12925766 t gcesareni Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. SIGNOR-118011 0.974 TFEB protein P19484 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; SIGNOR-276558 0.409 DLGAP2 protein Q9P1A6 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264590 0.849 TNFRSF13C protein Q96RJ3 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 BTO:0000776 24432023 f lperfetto Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures. SIGNOR-204364 0.7 MAP3K14 protein Q99558 UNIPROT MMP14 protein P50281 UNIPROT up-regulates activity phosphorylation 9606 27270613 t miannu A post-transcriptional process is indicated because we observed that NIK increases MT1-MMP phosphorylation and activity, but does not affect MT1-MMP mRNA expression (XREF_FIG and XREF_FIG).|NIK increases MT1-MMP pseudopodial localization and enzymatic activity. SIGNOR-279631 0.2 KAT2B protein Q92831 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-269610 0.2 FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 11717410 f Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255342 0.7 FXN protein Q16595 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262125 0.768 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187603 0.497 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 19951945 t gcesareni Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a. SIGNOR-161919 0.2 XL147 chemical CHEBI:71957 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252659 0.8 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 11602581 t gcesareni Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1. SIGNOR-111015 0.62 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 0.7 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl. SIGNOR-252786 0.2 ERCC1 protein P07992 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR form complex binding 9606 16338413 t miannu Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. SIGNOR-142989 0.953 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 0.446 PIN1 protein Q13526 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 BTO:0000150 23716601 t esanto Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated myc and its coactivators to select promoters during gene activation. SIGNOR-202134 0.573 PRKCZ protein Q05513 UNIPROT ADARB1 protein P78563 UNIPROT up-regulates activity phosphorylation Ser211 GDLSLSAsPVPASLA 9606 BTO:0001615 29694894 t miannu  Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.  SIGNOR-277392 0.2 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 0.345 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 0.596 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 0.2 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t gcesareni Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation SIGNOR-52583 0.883 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 0.93 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 t inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-270100 0.2 TBX3 protein O15119 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25595898 f miannu AKT phosphorylation potentiates the ability of TBX3 to repress the transcription of the E-cadherin gene SIGNOR-223537 0.41 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP4 protein P12644 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 19896409 f lperfetto BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others. SIGNOR-248842 0.582 RERE protein Q9P2R6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000932 28144959 t miannu In mammalian cells, RERE co‐immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over‐expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. SIGNOR-264486 0.318 CBX3 protein Q13185 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264495 0.2 RXRB protein P28702 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site SIGNOR-79449 0.274 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 14699954 t amattioni Neurotrophin binding to p75ntrhas also been shown to induce apoptosis SIGNOR-120555 0.836 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 0.904 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR MYCN protein P04198 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-269257 0.358 DNA-PK complex SIGNOR-C107 SIGNOR 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-264531 0.7 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A1/b1 integrin complex SIGNOR-C159 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-259000 0.43 JNK proteinfamily SIGNOR-PF15 SIGNOR YWHAZ protein P63104 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 Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190 SIGNOR-269980 0.2 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Ser332 TEDSTQTsDTATNST -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249680 0.2 SP3 protein Q02447 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867623 t Luana Sp1 and Sp3 Activate Transcription Driven by the AS Promoter SIGNOR-268020 0.2 RALGAPA2 protein Q2PPJ7 UNIPROT RalGAP2 complex SIGNOR-C469 SIGNOR form complex binding 10090 21148297 t miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. SIGNOR-269793 0.605 HDLBP protein Q00341 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 9925647 f miannu HBP/vigilin binds HDL and apoA-I on ligand blots; conceivably therefore apoA-I may interact with cytoplasmic vigilin promoting changes in cholesterol flux. SIGNOR-266692 0.7 USP1 protein O94782 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000567 SIGNOR-C302 18082604 t lperfetto The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells SIGNOR-263273 0.761 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBD1 protein Q9UJT1 UNIPROT down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259257 0.8 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 0.422 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 BTO:0000142 1411546 t gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-19240 0.742 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr347 RKKSWEVyQGVCQKG 9606 16226010 t lperfetto Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway. SIGNOR-141107 0.262 aclidinium chemical CHEBI:65346 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000131 19653626 t Luana This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. SIGNOR-258152 0.8 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 0.7 DACT1 protein Q9NYF0 UNIPROT DVL2 protein O14641 UNIPROT down-regulates binding 9606 16446366 t gcesareni Dapper 1 antagonizes wnt signaling by promoting dishevelled degradation SIGNOR-144053 0.791 MAPKAPK5 protein Q8IW41 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 t miannu Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity. SIGNOR-249708 0.295 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 0.357 IDH complex SIGNOR-C396 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266260 0.8 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO2 protein Q92813 UNIPROT up-regulates quantity by expression 9606 29892818 f scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. SIGNOR-267281 0.8 TERT protein O14746 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 f lperfetto Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers SIGNOR-252292 0.7 KRN-633 chemical CID:9549295 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193588 0.8 ABL2 protein P42684 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 33622779 f miannu Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. SIGNOR-266594 0.7 KLF4 protein O43474 UNIPROT STAT6 protein P42226 UNIPROT up-regulates 9606 BTO:0000801 22378047 f lperfetto KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPAR?) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-kappaB activation. SIGNOR-249569 0.345 CCKAR protein P32238 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257410 0.485 ASF1A protein Q9Y294 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates activity binding 9606 BTO:0002181 33503415 t miannu Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. SIGNOR-277621 0.311 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272710 0.768 IKBKB protein O14920 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser132 GDYFRYLsEVASGDN 9606 16024783 t gcesareni We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm. SIGNOR-138608 0.37 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 0.862 CHEK1 protein O14757 UNIPROT SNCB protein Q16143 UNIPROT unknown phosphorylation Tyr127 EDPPQEEyQEYEPEA 9606 21699177 t llicata Chk preferentially phosphorylates recombinant _-synuclein at tyrosine-127 SIGNOR-174590 0.2 HOXB8 protein P17481 UNIPROT TAGLN protein Q01995 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 t Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively SIGNOR-261642 0.2 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 alvocidib chemical CHEBI:47344 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192446 0.8 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 0.887 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 t lperfetto Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-187972 0.774 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 16085715 t miannu  In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms.  S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1. SIGNOR-276040 0.642 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB2 protein Q9Y5G2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265688 0.2 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT unknown phosphorylation Tyr715 LVMLGASyWYRARLH 9606 11741929 t llicata Hck, and to a lesser extent lck, phosphorylated the adam15 cytoplasmic domain in vitro in immune complex kinase assays. SIGNOR-112927 0.355 WNT7A protein O00755 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131900 0.59 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser533 ATGTGTFsPGASPGS 9606 BTO:0000567 31981797 t miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. SIGNOR-276834 0.436 MAPK1 protein P28482 UNIPROT YBX1 protein P67809 UNIPROT up-regulates activity phosphorylation 9606 19036157 t miannu ERK2 may also directly phosphorylate YB-1 and therefore promotes its ability to transactivate target genes. SIGNOR-279227 0.47 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 0.2 PPM1L protein Q5SGD2 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation -1 12556533 t miannu Co-immunoprecipitation experiments indicated that PP2Cepsilon associates stably with TAK1 and attenuates the binding of TAK1 to MKK4 or MKK6.|PP2Cepsilon dephosphorylated TAK1 in vitro. SIGNOR-277114 0.585 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 0.334 P2RY12 protein Q9H244 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256855 0.404 INTS14 protein Q96SY0 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261474 0.2 TFEB protein P19484 UNIPROT NAGLU protein P54802 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276543 0.324 CDK1 protein P06493 UNIPROT RAB11FIP3 protein O75154 UNIPROT up-regulates quantity phosphorylation Ser102 GPRGQLAsPDAPGPG 9606 BTO:0000567 22401586 t done miannu FIP3 is phosphorylated on S102 in a cell cycle-dependent manner. We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase. SIGNOR-273588 0.2 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 0.8 CCR6 protein P51684 UNIPROT MMP9 protein P14780 UNIPROT up-regulates activity 9606 BTO:0000584 15652956 t miannu We hypothesized that MIP-3alpha promotes pancreatic cancer invasion through the up-regulation of MMP-9, a Type 4 collagenase. SIGNOR-278042 0.2 NUP205 protein Q92621 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-262083 0.68 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 12588871 t lperfetto Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. hosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). SIGNOR-98275 0.346 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR up-regulates activity chemical activation 26083061 t lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function SIGNOR-262136 0.8 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 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-75637 0.791 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 t gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-180545 0.631 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247163 0.567 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 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 t FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time. SIGNOR-251476 0.2 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser102 LQTVIRTsPSSLVAF 26190112 t Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-253542 0.296 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 22298955 t gcesareni Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4. SIGNOR-195697 0.648 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 19029298 t llicata We show that pkd1-ser916 autophosphorylation does not necessarily correlate with pkd1 activity. Rather, autophosphorylation at ser916 is required for subsequent autophosphorylation at ser748. SIGNOR-182480 0.2 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 0.2 malonyl-CoA smallmolecule CHEBI:15531 ChEBI long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity precursor of 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267210 0.8 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr80 DQHSISYtLSRAQTV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276138 0.767 MMP23B protein O75900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272390 0.7 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2B protein P63146 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271334 0.756 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120092 0.311 COLGALT1 protein Q8NBJ5 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261153 0.429 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10116 BTO:0000575 15738637 t In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. SIGNOR-248444 0.285 HERC2 protein O95714 UNIPROT XPA protein P23025 UNIPROT down-regulates ubiquitination 9606 20304803 t miannu Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation SIGNOR-164595 0.385 KIT protein P10721 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 17949810 t miannu These results suggest that active KIT can directly phosphorylate tyrosine residues of beta-catenin. SIGNOR-278361 0.392 PAK4 protein O96013 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 BTO:0001130 20406887 t llicata We find that pak4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272. SIGNOR-164889 0.542 PRKCA protein P17252 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation 9606 22031842 t miannu PKC\u03b1 then phosphorylates and activates endothelial cell protein tyrosine phosphatase 1B (PTP1B) , . SIGNOR-279257 0.249 SRC protein P12931 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr679 DRPKDEVySKYYTPV 9606 12621061 t llicata Stat5 is activated by a broad spectrum of cytokines, as well as non-receptor tyrosine kinases, such as src. these conformational differences may in part be due to differential effects of prl and src on stat5b tyrosine phosphorylation, since src induced several additional sites of tyrosine phosphorylation of stat5b at residues other than tyr-699, including tyr-724 and tyr-679. SIGNOR-99002 0.578 LAMA4 protein Q16363 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253226 0.525 SSTR1 protein P30872 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256679 0.524 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250556 0.2 MYO9A protein B2RTY4 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260508 0.565 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t lperfetto Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation. SIGNOR-247324 0.411 LPAR1 protein Q92633 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256975 0.435 POLR1G protein O15446 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266155 0.2 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 8162590 t gcesareni The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. SIGNOR-36557 0.8 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Arg1046 HHAPLSPrTFHPLRS -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-263631 0.882 CDKN1A protein P38936 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000222 9388774 f gcesareni The upregulation of the cyclin-dependent kinase inhibitor p21 and the dephosphorylation of retinoblastoma protein (pRb) appear to be critical regulatory events for the establishment ,,, the postmitotic ... states [in myoblasts differentiating into mature myotubes] SIGNOR-241956 0.7 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 0.694 MRPS28 protein Q9Y2Q9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-267732 0.639 A9/b1 integrin complex SIGNOR-C166 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269015 0.7 AMER1 protein Q5JTC6 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21304492 t lperfetto Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomesThe generation of PtdIns(4,5)P2 in regions of receptor activity triggers the recruitment of Amer1 proteins, which in turn promote LRP6 phosphorylation by recruiting Axin/GSK3_ and CK1gamma to LRP6. SIGNOR-24265 0.478 SEMA3A protein Q14563 UNIPROT PLXNA4 protein Q9HCM2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261811 0.763 S100A9 protein P06702 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 9606 BTO:0001545 28137827 t miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 SIGNOR-261920 0.346 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity binding 9606 BTO:0002181 17761173 t Giulio We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. SIGNOR-260607 0.312 GSK3B protein P49841 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 GWSVHAPsSRRTTLC 9606 38442201 t miannu EEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. SIGNOR-277919 0.559 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser705 TPSAMKSsPQIPHQT 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-216805 0.382 GYPC protein P04921 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266034 0.362 MRGPRX1 protein Q96LB2 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257326 0.2 KIF3C protein O14782 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272536 0.7 TACR2 protein P21452 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257015 0.462 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 0.8 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190299 0.8 ITGAV protein P06756 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253209 0.869 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258509 0.8 HOXD12 protein P35452 UNIPROT MAF protein O75444 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221887 0.367 POLR2E protein P19388 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-266167 0.887 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16287866 t lperfetto Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-216876 0.419 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1. SIGNOR-105860 0.936 NUP153 protein P49790 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262069 0.737 JQ1 chemical CHEBI:137113 ChEBI BRDT protein Q58F21 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261990 0.8 precursor messenger RNA smallmolecule CHEBI:139356 ChEBI SF3b complex SIGNOR-C442 SIGNOR up-regulates activity relocalization 9606 32140746 t lperfetto The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation. SIGNOR-268413 0.8 REST protein Q13127 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 17453016 f NRSF represses neuronal differentiation by binding to conserved NRS elements (NRSEs) in gene promoters in non-neuronal cells, where it associates with one of several large repressor complexes, including the transcriptional co-repressor mSIN3a/b, nuclear receptor co-repressor 1 (N-CoR1), and coREST/histone deacetylase 2 (HDAC2). In this way, NRSF keeps neural-specific genes turned off in non-neuronal cells. SIGNOR-268622 0.7 KIF20B protein Q96Q89 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272528 0.7 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-41941 0.929 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential, SIGNOR-124047 0.522 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 15209375 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126076 0.609 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21193018 t lperfetto Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213]. SIGNOR-170854 0.716 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9927207 t llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. SIGNOR-64190 0.592 SAG protein P10523 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 25216516 t miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  SIGNOR-272844 0.412 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252849 0.911 Av/b2 integrin complex SIGNOR-C176 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269025 0.7 SNRPA1 protein P09661 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270655 0.773 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176754 0.8 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr421 RLPSSPVyEDAASFK -1 15169891 t lperfetto Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP. SIGNOR-246513 0.801 PRKACA protein P17612 UNIPROT CLDN3 protein O15551 UNIPROT unknown phosphorylation Thr192 PPREKKYtATKVVYS 9606 15905176 t llicata Our results suggest that claudin-3 phosphorylation by pka, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of tjs in this cancer. SIGNOR-137291 0.307 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257875 0.8 CIITA protein P33076 UNIPROT HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 f Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. SIGNOR-254006 0.509 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 10747897 t miannu We demonstrate that anisomycin- and tumor necrosis factor--induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase SIGNOR-250114 0.773 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser235 SPQDSPPsKASPAQD 9606 21215781 t lperfetto Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171018 0.763 KDM5B protein Q9UGL1 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates activity binding 9606 BTO:0000007 12657635 t miannu Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression SIGNOR-223878 0.403 3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol chemical CHEBI:94392 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition -1 19222165 t Luana 4 inhibited cloned hERG potassium ion channel repolarization with an IC50 comparable to other antimalarial agents in this class (Table 6). SIGNOR-257816 0.8 RPEL1 protein Q2QD12 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267066 0.8 IL1B protein P01584 UNIPROT GDF5 protein P43026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003742 19818765 f Regulation miannu GDF-5 is suppressed by IL-1beta and enhances TGF-beta3-mediated chondrogenic differentiation in human rheumatoid fibroblast-like synoviocytes. SIGNOR-251864 0.264 AKT1 protein P31749 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by destabilization phosphorylation Thr128 FIGEFAYtYAAMYDK 9606 BTO:0000007 31358653 t miannu Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.  SIGNOR-276869 0.369 MMP1 protein P03956 UNIPROT COL1A2 protein P08123 UNIPROT down-regulates quantity by destabilization cleavage Gly775 NGPPGPAgSRGDGGP -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272337 0.401 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser393 KTCQRKFsRSDHLKT 9606 9366517 t llicata Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo. SIGNOR-53176 0.341 GNB/GNG complex SIGNOR-C202 SIGNOR CACNA1B protein Q00975 UNIPROT down-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-265067 0.414 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 0.2 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr101 EGLSMGNyIGLINRI 9606 BTO:0001282 16373505 t PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. SIGNOR-251112 0.2 CASP3 protein P42574 UNIPROT SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 t amattioni Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. SIGNOR-57891 0.675 MAPK12 protein P53778 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity phosphorylation Ser200 YSGDSDAsSPRSNCS 10090 BTO:0005930 20026657 t miannu  We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity.  SIGNOR-276274 0.446 IKBKB protein O14920 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates phosphorylation Ser8 MEPAAGSsMEPSADW 9606 20152798 t lperfetto Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity SIGNOR-163801 0.396 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275957 0.2 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 11343802 t lperfetto Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation SIGNOR-107695 0.612 LNX1 protein Q8TBB1 UNIPROT CLDN17 protein P56750 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 t miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. SIGNOR-272900 0.294 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 0.8 CHRNA7 protein P36544 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 27167578 t Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. SIGNOR-253985 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270363 0.8 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 0.2 EDA protein Q92838 UNIPROT EDA2R protein Q9HAV5 UNIPROT up-regulates binding 9606 BTO:0001253 12084975 t gcesareni Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed. SIGNOR-90040 0.678 RNA Polymerase I complex SIGNOR-C390 SIGNOR rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 22260999 f lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266177 0.7 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-52863 0.823 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr498 YAFSSNIyTRGSHLD 9606 BTO:0000007 27738316 t miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. SIGNOR-263189 0.357 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 0.2 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates activity phosphorylation Ser1406 GAGGRRLsSFVTKGY 11986331 t miannu CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. SIGNOR-250344 0.307 CLK4 protein Q9HAZ1 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-273860 0.357 A6/b4 integrin complex SIGNOR-C174 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-269023 0.7 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser120 GRNIIHGsDSVESAE -1 8810265 t miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. SIGNOR-250300 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270430 0.8 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249324 0.763 CDC25A protein P30304 UNIPROT PKM protein P14618 UNIPROT up-regulates activity dephosphorylation Ser37 MCRLDIDsPPITARN 9606 27485204 t lperfetto Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop. SIGNOR-276967 0.487 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 0.569 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270696 0.831 PRKCE protein Q02156 UNIPROT SLC4A3 protein P48751 UNIPROT up-regulates activity phosphorylation Ser67 EKPSRSYsERDFEFH 9606 BTO:0000007 11739292 t lperfetto We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium. SIGNOR-249127 0.309 NDUFB11 protein Q9NX14 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262164 0.75 CAMK2A protein Q9UQM7 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser2137 RDLRRLYsVDAQGFL 10090 BTO:0003695 38001892 t miannu  we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.  SIGNOR-277871 0.272 MED11 protein Q9P086 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-266670 0.787 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191478 0.8 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70440 0.2 Class I MHC:Antigen complex SIGNOR-C426 SIGNOR Cytotoxic_T-lymphocyte_activation phenotype SIGNOR-PH195 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-267875 0.7 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 0.575 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR ID2 protein Q02363 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f Also comparable with ID1, RARα, RXR, PML, PLZF-RARα, and RARα/RXR did not transactivate the ID2 promoter, whereas PML-RARα did. Together, these data show that like ID1, ID2 may also be transactivated by PML-RARα without direct DNA binding of the fusion protein. SIGNOR-255727 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2C protein O00762 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271356 0.614 PRKDC protein P78527 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 9606 9109492 t miannu We show that DNA-PK phosphorylates and activates c-Abl in vitro. SIGNOR-279268 0.513 NGF protein P01138 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb. SIGNOR-85114 0.955 GTF2F2 protein P13984 UNIPROT POLR2E protein P19388 UNIPROT up-regulates activity binding 9534 11278533 t miannu Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. SIGNOR-261179 0.921 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 0.8 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001616 16670084 t gcesareni Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein. SIGNOR-245336 0.488 POLR1C protein O15160 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-266136 0.881 SPI1 protein P17947 UNIPROT ANXA1 protein P04083 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19428102 f miannu Identification of annexin 1 as a PU.1 target gene in leukemia cells. PU.1 is a master regulator, and critical for the developmen tof a common progenitor for lymphoid-myeloid cell lineages in the hematopoietic system. From microarray analysis, we found that several genes including annexin 1 were markedly induced in K562PU.1KD cells. Annexin 1 is a calcium- and phospholipid-binding protein and increased expression leads to the constitutive activation of extracellular signal-regulated kinase (ERK) SIGNOR-261688 0.2 SLC9A3R1 protein O14745 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates activity binding -1 9671706 t lperfetto The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor. SIGNOR-262598 0.598 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin SIGNOR-188869 0.576 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206673 0.8 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr144 MVPDEVEyLLKKVLS 9606 BTO:0000661 18976935 t lperfetto Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation. SIGNOR-253368 0.5 DRAM2 protein Q6UX65 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. SIGNOR-259146 0.306 125-L-serine-2-133-interleukin 2 (human reduced) smallmolecule SID:46508054 ChEBI IL2RB protein P14784 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-259389 0.8 (~{s})-(4-Fluoranyl-2-Propyl-Phenyl)-(1~{h}-Imidazol-2-Yl)methanol chemical CID:126961334 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition -1 28445455 t Simone Vumbaca The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. SIGNOR-261118 0.8 GSK3A protein P49840 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function. SIGNOR-252455 0.638 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70432 0.2 HIPK2 protein Q9H2X6 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser8 MEPAPARsPRPQQDP 9606 19015637 t llicata In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death. SIGNOR-182432 0.438 SNRPE protein P62304 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270657 0.728 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271805 0.8 BLOC-1 complex SIGNOR-C381 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 BTO:0000847 22203680 f lperfetto Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes SIGNOR-265939 0.7 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 0.831 ZAP70 protein P43403 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 BTO:0000782 9169414 t lperfetto In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation. SIGNOR-48854 0.363 PIN1 protein Q13526 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 19151708 t gcesareni Prolyl-isomerase pin1 interacts with notch1 and affects notch1 activation. Pin1 potentiates notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing notch1. pin1 potentiates notch1 cleavage by gamma-secretase SIGNOR-183461 0.384 TFPI protein P10646 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi SIGNOR-106353 0.257 TBP protein P20226 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263933 0.893 AMPK complex SIGNOR-C15 SIGNOR SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser122 YRNTGSIsGPKVNRP 10090 BTO:0003946 17341212 t miannu In the present study, we demonstrate that the metabolic sensing kinase AMPK (AMP-activated protein kinase) phosphorylates NKCC2 on Ser126 in vitro. Activation of AMPK in the MMDD1 (mouse macula densa-derived 1) cell line resulted in an increase in Ser126 phosphorylation in situ, suggesting that AMPK may phosphorylate NKCC2 in vivo. The functional significance of Ser126 phosphorylation was examined by mutating the serine residue to an alanine residue resulting in a marked reduction in co-transporter activity when exogenously expressed in Xenopus laevis oocytes under isotonic conditions. SIGNOR-263103 0.2 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser807 PGGNIYIsPLKSPYK 9606 1756735 t lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21552 0.688 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 0.409 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 12648465 t Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers. gcesareni Although ErbB-2 binds no known ligand, when recruited into heterodimers it increases ligand binding affinity SIGNOR-99569 0.588 PRKN protein O60260 UNIPROT PACRG protein Q96M98 UNIPROT down-regulates quantity by destabilization polyubiquitination -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-272889 0.2 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 t gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. SIGNOR-116166 0.644 DUSP3 protein P51452 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity dephosphorylation 9606 33777934 t lperfetto In the absence of DUSP3, these three residues remain phosphorylated and favor the dissociation equilibrium of NPM homo-oligomerization and/or its association with ARF, therefore promoting an early nuc|Therefore, here we focused on the molecular mechanisms used by DUSP3-NPM interaction to affect the abovementioned cellular responses and found out that DUSP3 dephosphorylates three tyrosine residues (Y29, Y67, and Y271) of NPM. SIGNOR-277005 0.2 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 0.2 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT up-regulates activity post translational modification Lys310 PFCKMVQkSLARLMF 9606 BTO:0000007 24315375 t desuccinylation lperfetto We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5 SIGNOR-267642 0.343 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT up-regulates activity phosphorylation Tyr42 VELDLHSyDLGIENR -1 34289383 t lperfetto Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity SIGNOR-267629 0.424 GSK3B protein P49841 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates phosphorylation Ser556 AQKSEGKsLPSSPSS 9606 16174773 t lperfetto Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1 SIGNOR-140609 0.487 BBOX1 protein O75936 UNIPROT carnitine smallmolecule CHEBI:17126 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269699 0.8 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 0.2 TNKS protein O95271 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263383 0.2 SLN protein O00631 UNIPROT ATP2A1 protein O14983 UNIPROT down-regulates activity binding 9606 28487373 t lperfetto These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity. SIGNOR-265929 0.55 CDK1 protein P06493 UNIPROT KMT5A protein Q9NQR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t miannu We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. SIGNOR-259832 0.2 RPS23 protein P62266 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262428 0.897 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194340 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation 9606 BTO:0000130 16778989 t inferred from 70% family members gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. SIGNOR-270187 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262219 0.8 SNX9 protein Q9Y5X1 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 t miannu Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes. SIGNOR-133892 0.788 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 t lperfetto We conclude that t687 is the primary site of threonine phosphorylation in psf. Gsk3 directly phosphorylates the splicing regulatory protein psf. In this phosphorylated form, psf is sequestered in a complex with trap150, precluding it from binding the ess1 sequence in cd45 alternatively spliced exons. Upon t?_Cell stimulation, reduced gsk3 activity leads to reduced psf phosphorylation, thereby releasing psf from trap150 and allowing it to participate in activation-induced cd45 exon skipping SIGNOR-168389 0.345 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 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-257983 0.8 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-167180 0.926 MCHR2 protein Q969V1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257268 0.587 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr287 PEETNNDyETADGGY -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262674 0.2 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Tyr394 QSQESEDySQPSTSS 9606 12110584 t gcesareni C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2. SIGNOR-90512 0.716 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 t miannu In contrast, we demonstrate for the first time that NEK6 phosphorylates SGK1 efficiently at its hydrophobic motif in vitro and peptide-mapping analysis indicates that this is the major site of phosphorylation (Fig 3). Ser377 is a more minor site of phosphorylation located in the kinase domain of SGK1, which has not been reported to undergo phosphorylation previously. the phosphorylation of the hydrophobic motif of SGK1 in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1 SIGNOR-262954 0.338 WNT9B protein O14905 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132111 0.623 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268608 0.267 PSMB5 protein P28074 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-263357 0.86 CDK2 protein P24941 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity phosphorylation Thr8 MSSILPFtPPVVKRL 9606 19201832 t miannu Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.|Moreover, CDK2 is the predominant cyclin-dependent kinase that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. SIGNOR-279678 0.488 PLK1 protein P53350 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Ser14 LEANADTsVEEESFG 9606 26811421 t miannu Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.|Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase\u2013mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. SIGNOR-278187 0.508 ZNF774 protein Q6NX45 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR up-regulates activity binding 9606 BTO:0000578 31659254 t miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. SIGNOR-265559 0.248 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 0.71 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 t miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. SIGNOR-28247 0.914 ARHGEF7 protein Q14155 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 21048939 t gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2 SIGNOR-169217 0.456 SMURF1 protein Q9HCE7 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 t lperfetto Recruitment of WW and HECT domain E3-ubiquitin ligases Smurf1 and 2 to induce type I receptor ubiquitination and subsequent receptor degradation; SIGNOR-153414 0.694 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 t inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-270195 0.2 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser178 TATETQCsVPIQCTD 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262716 0.743 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 14633703 t lperfetto Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-264659 0.441 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT up-regulates activity phosphorylation Thr281 QRRQASNtPSHIPIS 9606 BTO:0001938 16407227 t HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. SIGNOR-251269 0.463 WWTR1 protein Q9GZV5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199208 0.7 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249403 0.608 AKT1 protein P31749 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254372 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 t inferred from 70% family members gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-270051 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA4 protein Q9Y5G9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265675 0.2 TGFb proteinfamily SIGNOR-PF5 SIGNOR SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 29305973 t miannu Epithelial-mesenchymal transition (EMT) takes place, namely fibrosis, development and cancer. the process of EMT is integral to a number of physiological and disease states. TGF-β1 is a major effector of this process that activates various key transcription factors such as Snai1. SIGNOR-265251 0.2 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260112 0.656 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser634 TFLSPQCsPQHSPLG 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251249 0.397 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 0.501 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 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-251208 0.489 MECP2 protein P51608 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 t Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  SIGNOR-264675 0.29 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation Thr208 TFGNKLDtFCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122628 0.588 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-244754 0.2 PTPRG protein P23470 UNIPROT VCL protein P18206 UNIPROT down-regulates activity dephosphorylation Tyr822 KSFLDSGyRILGAVA -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254731 0.2 GUCY1A3-B3 complex SIGNOR-C140 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244105 0.8 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Ser215 KLDTFCGsPPYAAPE 9606 BTO:0000568 12879020 t lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. SIGNOR-104059 0.315 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252757 0.731 SMURF1 protein Q9HCE7 UNIPROT FAF2 protein Q96CS3 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272698 0.28 MFGE8 protein Q08431 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 22114683 f Giorgia Our study demonstrated the direct anti-inflammatory role of MFG-E8 in terms of attenuating TNF-α production in mouse peritoneal macrophages and RAW264.7 cells treated with LPS SIGNOR-260650 0.311 AMPK complex SIGNOR-C15 SIGNOR ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr356 GNPFDSKtEQGPQVD 10090 BTO:0000801 30375985 t lperfetto Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. SIGNOR-271862 0.252 MMP12 protein P39900 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. SIGNOR-263611 0.33 EGFR protein P00533 UNIPROT PLD2 protein O14939 UNIPROT up-regulates activity phosphorylation Tyr179 RLLTMSFyRNYHAMT 9606 9837959 t llicata Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold SIGNOR-251095 0.516 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 0.8 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Thr526 TNSFSAStGLSDMTA 10090 BTO:0000944 8662759 t llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. SIGNOR-250858 0.464 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 17299140 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-153031 0.929 Tuberoinfundibular peptide of 39 residues smallmolecule CHEBI:80275 ChEBI PTH2R protein P49190 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257576 0.8 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 0.261 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 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 signalin. SIGNOR-244761 0.2 NFIA protein Q12857 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268894 0.2 testosterone smallmolecule CHEBI:17347 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251553 0.8 GNGT1 protein P63211 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199144 0.409 apraclonidine chemical CHEBI:2788 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation -1 8784451 t miannu we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier. SIGNOR-258497 0.8 chloride smallmolecule CHEBI:17996 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-264989 0.7 MAPK3 protein P27361 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. SIGNOR-169004 0.313 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.925 IFNAR complex SIGNOR-C243 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity by expression 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260852 0.275 VX-765 chemical CID:53245642 PUBCHEM CASP1 protein P29466 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207770 0.8 SYBU protein Q9NX95 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 t miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. SIGNOR-264812 0.421 FBXO31 protein Q5XUX0 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 t miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. SIGNOR-277379 0.413 CREBBP protein Q92793 UNIPROT IRF9 protein Q00978 UNIPROT up-regulates activity acetylation Lys81 TGGPAVWkTRLRCAL 9606 BTO:0000007 17923090 t lperfetto CBP was also the most effective one among the acetyltransferases tested for catalyzing IRF9 acetylation in 293T cells. [²] Figure 5 (F) K81 acetylation is required for IRF9 dimerization between the N-terminal 1-118 and the C-terminal 340-393 regions. In the left panel, Myc-DBD (1- 118) of IRF9 was cotransfected with 118-393, 118-339, or 1-393 (FL) of IRF9 in 293T cells. Anti-IRF9 (C-terminal region) precipitates were analyzed with anti-Myc or anti-IRF9. Anti-IRF9 precipitates, prepared from 293T cells cotransfected with the C-terminal fragment 118-393 of IRF9 and Myctagged DBD of different forms, were analyzed with anti-Myc or anti-IRF9 (right panel). SIGNOR-217787 0.361 FGF2 protein P09038 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 15765505 f gcesareni Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development. SIGNOR-134512 0.439 CSNK1D protein P48730 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser247 KTFLSRHsLDMKFSY 9606 20699359 t lperfetto In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha SIGNOR-167476 0.324 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250555 0.2 motesanib chemical CHEBI:51098 ChEBI RET protein P07949 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194572 0.8 BBC3 protein Q9BXH1 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133814 0.552 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser880 YNVYGIEsVKI 9606 BTO:0000007 10501226 t lperfetto Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate. SIGNOR-249022 0.709 IRF2BP2 protein Q7Z5L9 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 t miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. SIGNOR-224073 0.631 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates activity phosphorylation Tyr139 Y-->K -1 18775312 t miannu In addition, we analyzed Fes SH2-kinase that had been autophosphorylated on the kinase activation segment (Y713) in complex with a substrate peptide. SIGNOR-277898 0.2 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249402 0.608 AXIN1 protein O15169 UNIPROT APC protein P25054 UNIPROT up-regulates activity binding 9606 BTO:0000038 9734785 t amattioni Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. SIGNOR-60043 0.944 F2RL1 protein P55085 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254855 0.2 CDK9 protein P50750 UNIPROT MYC protein P01106 UNIPROT down-regulates activity phosphorylation Ser62 S-->E 9606 31311847 t miannu CDK9 promotes phosphorylation of MYC on Ser 62 . SIGNOR-279024 0.54 PCM1 protein Q15154 UNIPROT NIN protein Q8N4C6 UNIPROT up-regulates relocalization 9606 12403812 t miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome SIGNOR-95077 0.406 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001061 14761977 t miannu  MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein. SIGNOR-272954 0.643 PTPRC protein P08575 UNIPROT FYN protein P06241 UNIPROT up-regulates activity dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 11909961 t On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction. SIGNOR-248352 0.73 PAK1 protein Q13153 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 21822311 t lperfetto Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin SIGNOR-175944 0.557 GOLGA3 protein Q08378 UNIPROT GOPC protein Q9HD26 UNIPROT up-regulates activity binding 9606 BTO:0000567 15951434 t miannu Golgin-160 belongs to the golgin family of Golgi-localized proteins, which have been implicated in Golgi structure and function. PIST (also known as GOPC, CAL, and FIG) has been implicated in the trafficking of a subset of plasma membrane proteins, supporting a role of golgin-160 in vesicular trafficking. binding of golgin-160, TC10, and syntaxin-6 to PIST may coordinate membrane trafficking of some plasma membrane proteins in cell types where these proteins are expressed. SIGNOR-261234 0.48 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser623 NRHSLPFsLPSQMEP 9606 BTO:0000782 11024037 t lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  SIGNOR-249055 0.322 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 t lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. SIGNOR-109878 0.617 calcitriol smallmolecule CHEBI:17823 ChEBI propan-2-ol smallmolecule CHEBI:17824 ChEBI up-regulates quantity precursor of 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270573 0.8 KAT5 protein Q92993 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity acetylation Lys247 MPFNKEPkWLFGTME 9606 34929314 t lperfetto Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. SIGNOR-267648 0.2 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates phosphorylation Thr182 KSGEPLStWCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122784 0.584 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 t gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 SIGNOR-143984 0.962 SP3 protein Q02447 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 t lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. SIGNOR-253351 0.2 MAPK14 protein Q16539 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity phosphorylation 10029 BTO:0005787 20887952 t The chromatin redistribution of PRC2 in differentiating SCs is regulated by the p38a kinase, which promotes the formation of a complex containing p38a, EZH2, and YY1, via direct phosphorylation of EZH2. SIGNOR-253599 0.326 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216777 0.845 RERE protein Q9P2R6 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity relocalization 9606 BTO:0000932 11331249 t miannu We detected RERE protein mainly in the nucleus, where it colocalizes with the promyelocytic leukemia protein in promyelocytic leukemia oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the proapoptotic protein BAX to PODS: This observation correlates with RERE-induced apoptosis, which occurs in a caspase-dependent manner. SIGNOR-264485 0.2 GNRHR protein P30968 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257064 0.25 SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR STAT3 protein P40763 UNIPROT down-regulates 9606 26194464 t mrosina In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255036 0.629 RPS6KA5 protein O75582 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 12628924 t gcesareni Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276. SIGNOR-99210 0.718 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 9927207 t llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. SIGNOR-64076 0.592 SPRY4 protein Q9C004 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR down-regulates 9606 BTO:0002283 20501643 f These results demonstrate that Spry4 expression reduces cell growth and anchorage-independent growth, two key characteristics of transformed cells. SIGNOR-278109 0.7 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 18097445 f gcesareni This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs.it is commonly thought that bax and bak form pores in membranes SIGNOR-160039 0.699 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr520 DNTPHTPtPFKNALE 9606 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250741 0.718 APOBEC3D protein Q96AK3 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261328 0.7 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-B receptor complex SIGNOR-C336 SIGNOR up-regulates activity chemical activation 9606 9872316 t brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. SIGNOR-263795 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR HTT protein P42858 UNIPROT unknown phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 12062094 t llicata We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1. SIGNOR-89696 0.2 CHRM5 protein P08912 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257291 0.385 RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 21133840 t simone vumbaca RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256022 0.553 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263782 0.7 TRIM65 protein Q6PJ69 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity ubiquitination Lys743 QWITENEkFAEVGVK 9606 28031478 t miannu These results indicate that TRIM65 promotes MDA5 ubiquitination at lysine 743, which is important for MDA5 activation. SIGNOR-278535 0.448 PIGF protein Q07326 UNIPROT PIGG protein Q5H8A4 UNIPROT up-regulates quantity by stabilization binding 10029 BTO:0000246 15632136 t miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. SIGNOR-261358 0.645 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr232 SQKKEGVyDVPKSQP 10090 BTO:0000938 11279201 t lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. SIGNOR-247084 0.42 CCP110 protein O43303 UNIPROT CALM1 protein P0DP23 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-265965 0.32 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-259430 0.2 PRKCB protein P05771 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276022 0.2 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273043 0.541 CHRM1 protein P11229 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256735 0.399 AKT1 protein P31749 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates activity phosphorylation Ser971 STRLRQQsSSSKGDS 9606 27858941 t miannu DAB2IP can be phosphorylated by RIP1 on Ser 604 within the PER domain, and by AKT1 on Ser 847 within the proline-rich domain. Although RIP1-mediated phosphorylation is stimulatory,40 a recent study reported that AKT-mediated phosphorylation inhibits DAB2IP functions SIGNOR-254780 0.497 CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260072 0.368 DOK1 protein Q99704 UNIPROT ITGB6 protein P18564 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257693 0.2 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192461 0.8 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 0.67 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 SIGNOR-C16 12105215 t gcesareni To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313 SIGNOR-90434 0.346 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5110 KAEAPLPsPKLEGEL 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-262764 0.256 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-189045 0.351 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR Helper_T-lymphocyte_activation phenotype SIGNOR-PH196 SIGNOR up-regulates 9606 31810556 f scontino Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies. SIGNOR-267874 0.7 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000567 9271440 t gcesareni The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424). SIGNOR-50607 0.384 PHLPP2 protein Q6ZVD8 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 BTO:0000182 21986499 t gcesareni We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro SIGNOR-248247 0.49 PRKACA protein P17612 UNIPROT HTT protein P42858 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2548 TRFGRKLsIIRGIVE -1 35908190 t miannu Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels. SIGNOR-277625 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA1 protein Q9Y5H4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265708 0.2 GSK3B protein P49841 UNIPROT PGR protein P06401 UNIPROT down-regulates quantity by destabilization phosphorylation Ser554 PDSEASQsPQYSFES 9606 23880761 t miannu Here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability. SIGNOR-276498 0.277 PTEN protein P60484 UNIPROT EGR2 protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260049 0.305 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR PI3K complex SIGNOR-C156 SIGNOR down-regulates 26721223 f Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. SIGNOR-255492 0.7 GUCY1B1 protein Q02153 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243980 0.2 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 RREB1 protein Q92766 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 17550981 f RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein. SIGNOR-253661 0.2 L-serine chemical CHEBI:17115 ChEBI glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity precursor of 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268222 0.8 KLF4 protein O43474 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding 9606 BTO:0000093 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267237 0.479 SSTR4 protein P31391 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256823 0.45 PLK1 protein P53350 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 32704044 t miannu In conclusion, we provide evidence that PLK1-dependent phosphorylation of FOXO1 induces its nuclear exclusion and negatively regulates FOXO1 transcriptional activity in PCa.|We previously demonstrated that PLK1 inhibits the transcriptional activity of FOXO1 by promoting its nuclear exclusion in U2OS cells . SIGNOR-278269 0.316 MAPK1 protein P28482 UNIPROT ATP1A1 protein P05023 UNIPROT down-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit. SIGNOR-262940 0.519 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr648 DVHNLDYyKKTTNGR 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3. SIGNOR-106734 0.2 ARID3A protein Q99856 UNIPROT Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 16738337 t lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene. SIGNOR-268531 0.2 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 f gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-114771 0.507 AKT proteinfamily SIGNOR-PF24 SIGNOR ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. SIGNOR-266357 0.2 WNT5A protein P41221 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-255651 0.834 FLT3 protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 t These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-255947 0.364 terazosin chemical CHEBI:9445 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 9606 9379432 t miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication SIGNOR-258670 0.8 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 0.502 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 0.807 PPP2CA protein P67775 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Thr175 GPEDQAVtEYVATRW 9606 16336213 t lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20% SIGNOR-142977 0.289 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 0.337 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck) SIGNOR-166358 0.349 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ABI1 protein Q8IZP0 UNIPROT down-regulates activity phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 t lperfetto We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly SIGNOR-264452 0.419 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts SIGNOR-249144 0.69 pimozide chemical CHEBI:8212 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258379 0.8 MAP3K10 protein Q02779 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates activity binding -1 12881483 t lperfetto we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2 SIGNOR-234599 0.333 CTH protein P32929 UNIPROT L-cysteine zwitterion smallmolecule CHEBI:35235 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-275824 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability. SIGNOR-244622 0.2 TACR1 protein P25103 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256919 0.2 TPO protein P07202 UNIPROT diiodine smallmolecule CHEBI:17606 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino TPO is considered the key enzyme in thyroid hormonogenesis. It catalyzes the oxidation of iodide that is necessary for the iodinationof the TG tyrosyl residues (the organification reaction). SIGNOR-266959 0.8 ID1 protein P41134 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241128 0.556 DYRK1A protein Q13627 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser403 WAKPKPLsPTSYMSP 9606 28235034 t miannu DYRK1A phosphorylation of NFATc1 and alphaA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation.|Here, we demonstrated that DYRK1A increased NFATc1 (NFATc1 and alphaA isoform) protein stability, in contrast to the decrease of NFATc2 protein stability by DYRK1A. SIGNOR-278277 0.429 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 0.307 NEDD4 protein P46934 UNIPROT SAG protein P10523 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25216516 t miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  SIGNOR-272843 0.373 UBE2S protein Q16763 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000567 19822757 t lperfetto Here, we identify the highly conserved Ube2S as a regulator of human and Drosophila APC/C. Ube2S functions as a K11-specific chain elongating E2 of APC/C, which depends on chain initiation by UbcH10. Together, UbcH10 and Ube2S are required for the degradation of all APC/C substrates tested so far, spindle formation, and progression of cells through mitosis. SIGNOR-265080 0.67 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 22056878 t Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. gcesareni In estrogen-receptor-negative cellular models showing coamplification of erbb2 and rara, simultaneous targeting of the corresponding gene products with combinations of lapatinib and atra causes synergistic growth inhibition, cyto-differentiation and apoptosis. SIGNOR-177081 0.8 QRICH1 protein Q2TAL8 UNIPROT IARS1 protein P41252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269406 0.2 LPAR3 protein Q9UBY5 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257406 0.437 BCR-Dl complex SIGNOR-C436 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268442 0.715 NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256380 0.2 THRA protein P10827 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 t gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-133240 0.432 DUSP26 protein Q9BV47 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates activity dephosphorylation 9606 28701747 t miannu NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells SIGNOR-277104 0.2 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1P5 protein Q5VTE0 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269389 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273081 0.633 CREB5 protein Q02930 UNIPROT CFB protein P00751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002809 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253802 0.2 PSMF1 protein Q92530 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity binding 9606 BTO:0000007 23622245 t lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. SIGNOR-263341 0.526 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-101310 0.34 JAK2 protein O60674 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Tyr641 KNEFISEyCGEIISQ 9606 24469040 t lperfetto Oncogenic y641 mutations in ezh2 prevent jak2/beta-trcp-mediated degradationbeta-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs beta-trcp-mediated ezh2 degradation. SIGNOR-202711 0.534 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 0.2 HRAS protein P01112 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. SIGNOR-175189 0.759 CRHR1 protein P34998 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 f lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). SIGNOR-268612 0.653 PIK3CG protein P48736 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates binding 9606 9768361 t gcesareni Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k. SIGNOR-60567 0.632 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 19107194 t lperfetto We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells SIGNOR-216841 0.475 DLG5 protein Q8TDM6 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270893 0.314 MINK1 protein Q8N4C8 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates binding 9606 9230439 t miannu Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density. SIGNOR-49869 0.284 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16611981 t gcesareni Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites SIGNOR-146112 0.568 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 0.38 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 t Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. SIGNOR-260305 0.561 NUMA1 protein Q14980 UNIPROT TUBB3 protein Q13509 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-116979 0.2 AKT1 protein P31749 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates activity phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0000567 21620836 t miannu A reciprocal immunoprecipiation with anti-phospho-Akt substrate antibody followed by immunoblotting with anti-FLAG antibodies confirmed these findings (Fig. 1C). We concluded that Fbw7 is phosphorylated at S227 in vivo. Phosphorylation of Fbw7 is required for its biological activity. SIGNOR-276328 0.41 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249281 0.396 CREB5 protein Q02930 UNIPROT TNFRSF11B protein O00300 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253812 0.2 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 0.92 PRKCG protein P05129 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-97558 0.702 STAT3 protein P40763 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255240 0.317 COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 9606 26497135 t miannu The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome. SIGNOR-270794 0.316 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273062 0.633 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.914 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248808 0.855 PPM1A protein P35813 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2C_ dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity SIGNOR-252724 0.324 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201538 0.96 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258842 0.8 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser358 ELRKTQTsMSLGTTR 10090 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266427 0.753 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 12514131 t gcesareni We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2. SIGNOR-96955 0.329 clozapine chemical CHEBI:3766 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258835 0.8 VRK1 protein Q99986 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17938195 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis. SIGNOR-158436 0.2 MAPK3 protein P27361 UNIPROT SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation Thr622 LGTQVPGtPPPKYNT -1 11805112 t lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-249449 0.28 P2RY6 protein Q15077 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257277 0.401 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 0.316 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SLC25A27 protein O95847 UNIPROT up-regulates quantity by expression transcriptional regulation 20385226 t lperfetto We present the first direct evidence that UCP4 is regulated by NF-kappaB, mediated via a functional NF-kappaB site in its promoter region, and that UCP4 has a significant role in NF-kappaB prosurvival signaling, mediating its protection against MPP(+) toxicity.|NF-kappaB inhibition significantly suppressed the MPP(+)-induced increase in UCP4 expression. SIGNOR-268984 0.2 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 BTO:0000887;BTO:0001103 19620279 t miannu We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. SIGNOR-202045 0.652 resveratrol chemical CHEBI:27881 ChEBI AHR protein P35869 UNIPROT down-regulates activity chemical inhibition -1 9865727 t Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. SIGNOR-253640 0.8 MAP3K11 protein Q16584 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001538 9003778 t lperfetto Immunoprecipitated mlk-3 catalyzed the phosphorylation of sek1 in vitro, and co-transfected mlk-3 induced phosphorylation of sek1 and mkk3 at sites required for activation, suggesting direct regulation of these protein kinases. SIGNOR-45788 0.492 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 0.848 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 0.708 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 11965546 t lperfetto Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. SIGNOR-217204 0.354 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2C protein Q06413 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216963 0.288 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 0.643 LYN protein P07948 UNIPROT DOK3 protein Q7L591 UNIPROT up-regulates activity phosphorylation 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-268447 0.409 DLK1 protein P80370 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 t gcesareni Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. SIGNOR-172830 0.518 ID1 protein P41134 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241107 0.634 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 9606 20570526 t Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], SIGNOR-257850 0.8 PRKACA protein P17612 UNIPROT ARFGEF1 protein Q9Y6D6 UNIPROT up-regulates activity phosphorylation Ser883 EIAGKKIsMKETKEL 9606 BTO:0000599 16467138 t lperfetto Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site SIGNOR-272146 0.2 TBX5 protein Q99593 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255253 0.267 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-250793 0.322 BCAR1 protein P56945 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 BTO:0000182 27447856 t lperfetto One such SH2-domain containing protein is the p85 subunit of PI3K, as its docking with tyrosine-phosphorylated p130cas activates the p110alpha subunit| tyrosine-165 and tyrosine-128 on p130cas both are phosphorylated to a greater extent in parental versus paxillin Y88F mutan SIGNOR-263980 0.563 BCL7C protein Q8WUZ0 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-270715 0.503 ITCH protein Q96J02 UNIPROT TRPC4 protein Q9UBN4 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 17110928 t miannu Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. SIGNOR-272624 0.35 PDHA1 protein P08559 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266544 0.81 TAF7 protein Q15545 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263928 0.9 EGR1 protein P18146 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 12456801 t Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. SIGNOR-254265 0.2 FOXL2 protein P58012 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254178 0.392 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.632 ACO1 protein P21399 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266245 0.8 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. SIGNOR-156856 0.671 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr806 TPHYGSQtPLHDGSR 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-143939 0.776 GNAQ protein P50148 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152609 0.282 arachidonic acid smallmolecule CHEBI:15843 ChEBI PTGS2 protein P35354 UNIPROT up-regulates 9606 15878913 f miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255394 0.8 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 26971449 t lperfetto We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system. SIGNOR-253393 0.319 KCNQ2 protein O43526 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265982 0.8 PINK1 protein Q9BXM7 UNIPROT HIF3A protein Q9Y2N7 UNIPROT down-regulates activity phosphorylation Thr12 LQRARSTtELRKEKS 9606 BTO:0000793 27551449 t Parkinson miannu Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. SIGNOR-263090 0.347 ZNF318 protein Q5VUA4 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 16469430 t Monia Using different promoters and cells, we confirmed that AR-mediated transactivation was repressed by TZF in a dose-dependent manner (Fig. 1A and B). Endogenous ARmediated transactivation was also inhibited by expression of TZF; These results indicate that amino acid residues 512–663 are essential for the repressive effect of TZF on AR-mediated transactivation. SIGNOR-261187 0.372 RXRB protein P28702 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16674 0.722 EIF2B5 protein Q13144 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269128 0.877 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-92603 0.763 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr72 PLLPPSAtGPDATVG 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-96414 0.666 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120192 0.316 NAMPT protein P43490 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI up-regulates quantity chemical modification 9606 12555668 t gcesareni Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi SIGNOR-238602 0.8 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81137 0.542 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser410 RKDSLDDsGSCLSGS 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248988 0.39 SYK protein P43405 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr955 ADAEEAMyQNVDGRV 9606 24525236 t miannu Only two mutants, FLT3-KD (V5) Y768A and Y955A, were resistant to SYK mediated FLT3 phosphorylation, suggesting that SYK directly phosphorylates FLT3 at sites Y768 and Y955 (XREF_FIG).|SYK Enhances FLT3 WT and Mutant Activation by Phosphorylation of Residues Y768 and Y955. SIGNOR-278430 0.407 LPAR6 protein P43657 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256725 0.2 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24321385 t miannu We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells SIGNOR-259973 0.283 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr341 GQRDSSYyWEIEASE 10090 BTO:0001482 8876196 t  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. SIGNOR-251362 0.617 GSK3B protein P49841 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264874 0.2 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites. SIGNOR-21316 0.485 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Ser53 HPQLHIEsKIYKMMQ -1 31096047 t miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. SIGNOR-277451 0.2 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 7822264 t llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. SIGNOR-250626 0.427 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-169682 0.422 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 0.292 SMURF1 protein Q9HCE7 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR down-regulates ubiquitination 9606 22298955 t Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps SIGNOR-269847 0.769 SERPINA1 protein P01009 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 t lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). SIGNOR-263515 0.33 PTK2 protein Q05397 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Tyr35 ICGPEENyPSLQMSS 9606 BTO:0000007 22493428 t miannu  In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. SIGNOR-276409 0.274 ITGB1 protein P05556 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253184 0.781 CUL3 protein Q13618 UNIPROT TNFAIP1 protein Q13829 UNIPROT up-regulates activity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264232 0.461 PRKCZ protein Q05513 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization phosphorylation Ser45 GATTTAPsLSGKGNP 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). SIGNOR-276878 0.599 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates activity phosphorylation Ser99 KNKGKGFsVVADTPE -1 12432067 t miannu Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146 SIGNOR-250075 0.306 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 0.686 SLBP protein Q14493 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265373 0.2 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser838 LVFDYEGsGSEAASL 10090 BTO:0000944 10671552 t llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | All mutants showed a clear reduction in phosphorylation. Phosphorylation was completely abolished in the single mutant S855A and the double mutant S853/855A, and phosphorylation in S840A and S853A mutants was reduced to 43 and 28% that of wt GST-ECT. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. SIGNOR-250839 0.401 EIF3F protein O00303 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates deubiquitination 9606 21124883 t gcesareni The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor. SIGNOR-254327 0.421 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS1 protein O95835 UNIPROT down-regulates 10090 22863277 f milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-198517 0.8 DDX28 protein Q9NUL7 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261229 0.7 cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 10116 BTO:0001103 15829723 t apalma On one hand, inhibition of calcineurin with cyclosporin A (CsA) significantly reduced the growth of both the slow/type I soleus muscle and fast/type II plantaris muscle in normal, ambulatory rats SIGNOR-255102 0.8 pemetrexed disodium chemical CHEBI:63722 ChEBI ATIC protein P31939 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-259292 0.8 TFEB protein P19484 UNIPROT CALCOCO1 protein Q9P1Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276784 0.2 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 18377662 t Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 SIGNOR-248475 0.668 LAMA4 protein Q16363 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-253223 0.506 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-269969 0.2 GRPR protein P30550 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257046 0.268 MARK2 protein Q7KZI7 UNIPROT RAB11FIP2 protein Q7L804 UNIPROT up-regulates phosphorylation Ser227 QRLSSAHsMSDLSGS 9606 BTO:0000671 16775013 t lperfetto We identified the kinase that phosphorylated rab11-fip2 as mark2/emk1/par-1balpha (mark2), and recombinant mark2 phosphorylated rab11-fip2 only on serine 227. In calcium switch assays, cells expressing rab11-fip2(s227a) showed a defect in the timely reestablishment of p120-containing junctional complexes. SIGNOR-147118 0.42 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277177 0.2 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 0.2 UTS2R protein Q9UKP6 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257164 0.265 TRADD protein Q15628 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 10629108 t amattioni Tradd mediates recruitment of traf1/2 SIGNOR-73913 0.694 p38 proteinfamily SIGNOR-PF16 SIGNOR KRT8 protein P05787 UNIPROT up-regulates phosphorylation 9606 11788583 t inferred from 70% family members lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-270125 0.2 TNFSF12 protein O43508 UNIPROT MYH3 protein P11055 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000165 17314137 t miannu TWEAK induces ubiquitination of MyHCf and expression of atrogin-1 and MuRF1 in myotubes. our data show that TWEAK rapidly increases the conjugation of ubiquitin to MyHCf (Fig. 3A) and ubiquitination preceded the degradation of MyHCf (Fig. 2C and Fig. 3A). SIGNOR-272628 0.2 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 10737616 t lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. SIGNOR-249418 0.566 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270412 0.8 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr387 LPWDLWTtSTDLVQP 9606 BTO:0000567 16945112 t lperfetto Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin. SIGNOR-149318 0.2 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t gcesareni We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. SIGNOR-120330 0.518 CSNK2A1 protein P68400 UNIPROT MME protein P08473 UNIPROT down-regulates phosphorylation Ser6 sQMDITDI 9606 20957047 t lperfetto The cytoplasmic n-terminal domain of nep interacts with the phosphatase and tensin homologue deleted on chromosome 10 (pten) thereby regulating intracellular signaling via akt. Ser 6 is efficiently phosphorylated by protein kinase ck2. The phosphorylation of the cytoplasmic domain of nep inhibits its interaction with pten. SIGNOR-168673 0.323 PRKCA protein P17252 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276025 0.2 SARS1 protein P49591 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270495 0.8 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates activity chemical inhibition 9606 7566123 t Monia Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin. SIGNOR-261074 0.8 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 0.2 BCL7B protein Q9BQE9 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-270721 0.45 PTPRO protein Q16827 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 25301722 t lperfetto SRC activation triggered by loss of PTPRO leads to c-CBL degradation.|These data corroborate that PTPRO directly dephosphorylates SRC at Y416. SIGNOR-277004 0.422 MAPK1 protein P28482 UNIPROT RBFOX2 protein O43251 UNIPROT unknown phosphorylation Thr7 tPGYHGFP 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262761 0.2 Calcineurin complex SIGNOR-C155 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-252334 0.409 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 0.58 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-30905 0.79 WNT9A protein O14904 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-132076 0.64 MARCHF9 protein Q86YJ5 UNIPROT ICAM1 protein P05362 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17174307 t miannu MARCH-IX expression causes ubiquitination and downregulation of ICAM-1 and a short alternative transcript of MARCH-IX lacking the RING-CH domain, termed MARCH-IX RINGless, is shown to act as a positive regulator of MARCH-IX activity.|MARCH-IX mediates ubiquitination and downregulation of ICAM-1. SIGNOR-278821 0.2 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser490 QSTEPALsQIVMAPS 9606 15916964 t lperfetto Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif) SIGNOR-137619 0.566 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). SIGNOR-272741 0.403 Gbeta proteinfamily SIGNOR-PF4 SIGNOR DUSP1 protein P28562 UNIPROT down-regulates phosphorylation 9606 16286470 t inferred from 70% family members lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-270093 0.2 CYP11B2 protein P19099 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268680 0.8 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248599 0.2 RIPK3 protein Q9Y572 UNIPROT PDH complex SIGNOR-C402 SIGNOR up-regulates activity phosphorylation -1 29358703 t miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. SIGNOR-268065 0.2 PAX7 protein P23759 UNIPROT KMT2D protein O14686 UNIPROT up-regulates binding 9606 SIGNOR-C88 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198629 0.304 GSK3B protein P49841 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser638 PRVDLHTsGEHSELV 9606 BTO:0001615 29179460 t lperfetto GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression| SIGNOR-264890 0.2 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity dephosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 20080667 t miannu DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation. SIGNOR-254754 0.435 SH3GL3 protein Q99963 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-263884 0.7 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr331 LTEDSTQtSDTATNS -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249676 0.2 CSNK2A1 protein P68400 UNIPROT PIN4 protein Q9Y237 UNIPROT down-regulates activity phosphorylation Ser19 AGKGGAAsGSDSADK 9606 BTO:0000567 12860119 t lperfetto As proved by MALDI-TOF mass spectrometry and MS/MS fragmentation, hPar14 is phosphorylated at Ser19 in vitro and in vivo. In human HeLa cells the protein is most likely modified by casein kinase 2 (CK2). |In contrast to wild-type hPar14, the in vitro DNA-binding affinity of the Glu19 mutant is strongly reduced, suggesting that only the dephosphorylated protein is the active DNA-binding form of hPar14 in the nucleus. SIGNOR-265753 0.326 TP63 protein Q9H3D4 UNIPROT SUN1 protein O94901 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005098 28595999 t lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. SIGNOR-263278 0.2 MYC protein P01106 UNIPROT HLA-E protein P13747 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-254604 0.2 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 0.2 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 0.782 GSK3B protein P49841 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Ser186 APRTHPYsPKSEAPR 9606 BTO:0001583 21873430 t miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. SIGNOR-276354 0.286 GSK3B protein P49841 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser211 SSVKLRGsSLFMDTE -1 24817118 t miannu Serine 211 phosphorylation occurred under control conditions in the absence of CK1δ and in the presence of GSK3-β (Fig. 5, D and E). SIGNOR-276632 0.329 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser821 YLRQFSGsLKPEDAE 9534 BTO:0000298 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249233 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL11 protein P51671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16604092 f miannu Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. SIGNOR-254661 0.262 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 0.837 PRKCA protein P17252 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates activity phosphorylation Ser39 VAYGVREsVFTVEGG 9606 28555617 t miannu PKC\u03b1 phosphorylates PHB2-S39. SIGNOR-279256 0.2 SMARCB1 protein Q12824 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270747 0.836 USF2 protein Q15853 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 f miannu Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation. SIGNOR-254656 0.2 SH3PXD2B protein A1X283 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264707 0.347 MTOR protein P42345 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates activity phosphorylation Ser571 KGEDLVGsLNGGHAN 9606 BTO:0001938 26139536 t miannu MTOR phosphorylates UVRAG at serine 550 and serine 571 SIGNOR-276919 0.408 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity methylation 9606 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-265349 0.2 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 0.85 AKT proteinfamily SIGNOR-PF24 SIGNOR HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. SIGNOR-186772 0.2 MCU_MICU2_variant complex SIGNOR-C502 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270878 0.8 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser529 KGAKVFGsLERGLDK 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141018 0.2 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 8754811 f fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively SIGNOR-210068 0.8 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 0.8 QRICH1 protein Q2TAL8 UNIPROT WARS1 protein P23381 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269410 0.2 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 0.345 PTPRK protein Q15262 UNIPROT PROM1 protein O43490 UNIPROT down-regulates activity dephosphorylation -1 30947381 t miannu PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo. SIGNOR-277133 0.2 amitriptyline chemical CHEBI:2666 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258702 0.8 NAE complex SIGNOR-C131 SIGNOR ANAPC2 protein Q9UJX6 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243175 0.405 CITED2 protein Q99967 UNIPROT MMP1 protein P03956 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003859 12960175 f miannu CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway. SIGNOR-253778 0.356 canertinib chemical CHEBI:61399 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258200 0.8 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 7901013 t The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax SIGNOR-34686 0.267 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr904 EEEGRDEyDEVAMPV -1 10942405 t Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport. SIGNOR-251414 0.338 SLC24A4 protein Q8NFF2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264392 0.8 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser604 FQSTSVKsPKTVSPP 9606 23188829 t miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. SIGNOR-263055 0.2 SOCS4 protein Q8WXH5 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates activity 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-272141 0.493 HTR1B protein P28222 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257207 0.25 tyrosine smallmolecule CHEBI:18186 ChEBI Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity precursor of 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270524 0.8 STUB1 protein Q9UNE7 UNIPROT S100P protein P25815 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 23344957 t miannu S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway. SIGNOR-272919 0.292 STAT3 protein P40763 UNIPROT SALL4 protein Q9UJQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 19151334 f miannu We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. SIGNOR-255244 0.582 THBS1 protein P07996 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252271 0.7 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 0.307 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser183 CPHHERCsDSDGLAP 9606 22611192 t gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). SIGNOR-197598 0.719 TEAD4 protein Q15561 UNIPROT CCN2 protein P29279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33358571 t miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter SIGNOR-277686 0.2 ELMO2 protein Q96JJ3 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001909 25533347 t miannu We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth. SIGNOR-266821 0.583 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 SIGNOR-250011 0.346 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 BTO:0000007 22724072 t PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 SIGNOR-270345 0.2 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN1 protein Q9GZT9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 t lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. SIGNOR-261991 0.8 MAPK1 protein P28482 UNIPROT PDE4C protein Q08493 UNIPROT down-regulates phosphorylation Ser641 YQSKIPRsPSDLTNP 9606 11030732 t The effect has been demonstrated using Q08493-2 gcesareni The short-form pde4b2 isoenzyme was activated by erk2 phosphorylation. sub-family selective actions in the ability of erk2 map kinase to phosphorylate and regulate the activity of pde4 cyclic amp-specific phosphodiesterases SIGNOR-83187 0.256 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser39 FMRLRRLsTKYRTEK 9606 7520867 t miannu Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435 / phosphorylation of ser39 in vitro decreases the activity of ptp-pest by reducing its affinity for substrate. SIGNOR-27300 0.322 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276100 0.264 PRKCB protein P05771 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity phosphorylation Ser582 LWHFRYEsLKHPKAY 9606 BTO:0000007 23824069 t miannu  Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ. SIGNOR-276496 0.501 ARHGEF4 protein Q9NR80 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260531 0.667 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 0.2 NDFIP1 protein Q9BT67 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 26363003 t SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. SIGNOR-260997 0.589 ROBO3 protein Q96MS0 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 t miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268379 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-217344 0.7 IL2 protein P60568 UNIPROT IL2RB protein P14784 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-144540 0.869 PHF20 protein Q9BVI0 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267159 0.683 EXOC4 protein Q96A65 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-270779 0.923 UBE2I protein P63279 UNIPROT ETV5 protein P41161 UNIPROT down-regulates sumoylation 9606 15857832 t miannu Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription. SIGNOR-135850 0.266 SPAST protein Q9UBP0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates cleavage -1 15716377 f Gianni Using real-time imaging, we show that Spastin severs microtubules when added to permeabilized, cytosol-depleted cells stably expressing GFP-tubulin. SIGNOR-269046 0.7 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 f These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs SIGNOR-253602 0.371 EZR protein P15311 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 f miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. SIGNOR-268432 0.7 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 20864032 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-168040 0.2 E4F1 protein Q66K89 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity ubiquitination Lys321 SSPQPKKkPLDGEYF 9606 BTO:0001938 17110336 t miannu E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription. SIGNOR-271395 0.608 CBL protein P22681 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination Lys970 GMEYLGTkRYIHRDL 9606 28676638 t miannu K63 linked poly-ubiquitination on K970 of JAK2 kinase domain is promoted by Cbl. SIGNOR-278538 0.587 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252830 0.911 CASP7 protein P55210 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261757 0.342 ECM stimulus SIGNOR-ST20 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259035 0.7 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 15084608 t lperfetto Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. SIGNOR-124236 0.668 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. SIGNOR-181628 0.2 BIRC2 protein Q13490 UNIPROT ENDOG protein Q14249 UNIPROT up-regulates activity ubiquitination 9606 25139236 t miannu Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death. SIGNOR-278605 0.468 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser50 KQINKRAsGQAFELI 9534 BTO:0000298 9525956 t miannu Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation SIGNOR-250056 0.309 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. SIGNOR-250272 0.609 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser196 EKSPSVCsPLNMTSS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276107 0.286 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 0.365 RNF7 protein Q9UBF6 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271450 0.2 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 0.619 ARIH1 protein Q9Y4X5 UNIPROT EIF4E2 protein O60573 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 14623119 t miannu Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7. Thus, by promoting the ubiquitin-mediated degradation of 4EHP, HHARI may have a role in both protein degradation and protein translation. SIGNOR-268848 0.678 CYSLTR1 protein Q9Y271 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256883 0.2 MAPK11 protein Q15759 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target SIGNOR-65586 0.756 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183608 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2G1 protein P62253 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271349 0.714 EP300 protein Q09472 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 f lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. SIGNOR-254097 0.2 SLC12A1 protein Q13621 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264635 0.8 ATOH1 protein Q92858 UNIPROT HES6 protein Q96HZ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17826772 f miannu Electrophoretic mobility shift assays and luciferase assays show that ATOH1 activates HES6 transcription through binding to three clustered E boxes of its promoter. SIGNOR-253754 0.439 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0002181 11726515 t irozzo However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation. SIGNOR-255820 0.2 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264920 0.8 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 t esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. SIGNOR-252586 0.559 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276117 0.629 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation -1 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258442 0.8 AKT2 protein P31751 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by stabilization phosphorylation Ser41 KRPLRAPsPEPAAPR -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277359 0.27 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269352 0.726 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates binding 9606 11130076 t gcesareni Here we demonstrate that irsp53, a substrate for insulin receptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex. SIGNOR-85302 0.739 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258714 0.8 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Thr145 AGNKRLStIDESGSI 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250589 0.78 GSK3B protein P49841 UNIPROT NEFH protein P12036 UNIPROT down-regulates phosphorylation Ser503 GGEEETKsPPAEEAA 9606 12130654 t lperfetto Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment SIGNOR-90668 0.302 PRKG2 protein Q13237 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr430 LEIIRGRtKQHGQFS -1 35226996 t miannu Recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells. SIGNOR-277589 0.2 PPP3CA protein Q08209 UNIPROT NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176376 0.538 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR E2F5 protein Q15329 UNIPROT up-regulates activity phosphorylation Thr261 SQSLTPVtPQKSSMA 9606 10783242 t miannu Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. SIGNOR-262732 0.641 BRCA2 protein P51587 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263256 0.8 GSK3A protein P49840 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser280 FHCCQCTsVETVTEL 10116 BTO:0003324 30745182 t miannu Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARα targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation.  SIGNOR-277431 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272508 0.2 cis-(z)-Flupenthixol chemical CHEBI:10454 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258715 0.8 chelerythrine chemical CHEBI:78373 ChEBI MAPK8 protein P45983 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-190964 0.8 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 19759537 t gcesareni Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2. SIGNOR-188057 0.8 TAOK1 protein Q7L7X3 UNIPROT STK4 protein Q13043 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-201324 0.368 AP1G2 protein O75843 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity binding 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-272636 0.401 TGFBR1 protein P36897 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates phosphorylation 9606 12543979 t gcesareni This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead. SIGNOR-97626 0.522 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates phosphorylation Thr159 DGSEPTKtPGRTSST 9606 BTO:0000938 20513426 t llicata Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34. SIGNOR-165772 0.357 SRC protein P12931 UNIPROT HCN2 protein Q9UL51 UNIPROT up-regulates activity phosphorylation Tyr476 LDSSRRQyQEKYKQV 9606 BTO:0000007 26280531 t miannu We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity. SIGNOR-263199 0.267 BCL2L11 protein O43521 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260426 0.7 PTPRJ protein Q12913 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 25386896 t lperfetto Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases. SIGNOR-276992 0.519 AKT2 protein P31751 UNIPROT SRSF5 protein Q13243 UNIPROT up-regulates activity phosphorylation Ser86 GRGRGRYsDRFSSRR 10116 15684423 t miannu Here we show that Akt2 kinase phosphorylated SRp40 in vivo and in vitro. Mutation of Ser86 on SRp40 blocked in vitro phosphorylation. SIGNOR-262633 0.362 MFGE8 protein Q08431 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 10116 31958465 t miannu Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5. SIGNOR-260644 0.525 TRAF6 protein Q9Y4K3 UNIPROT ULK1 protein O75385 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 23524951 t lperfetto AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. SIGNOR-273000 0.548 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000150 18492217 t gcesareni Numb can actually interact in vivo with endogenous mdm2 and p53, resulting in a trimeric complex between the three proteins [10]. This interaction appears to regulate the stability of p53, as reduction of numb levels by rna interference (rnai) causes a decrease in the half-life of p53 and consequently a reduction in steady-state levels of the protein. Consistent with this observation, overexpression of numb increases the level of p53 in both unstressed and stressed cells. SIGNOR-178668 0.515 NFAT5 protein O94916 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 22266867 t done miannu  As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009). SIGNOR-274115 0.478 KAT5 protein Q92993 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys21 GGAKRHRkVLRDNIQ 9606 12776177 t lperfetto Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals. SIGNOR-262061 0.2 N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide chemical CHEBI:94771 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193513 0.8 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser698 PEWPRRAsCTSSTSG -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250883 0.329 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. SIGNOR-255104 0.868 PRKACA protein P17612 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation Ser119 YGPPSRRsENRVVVS 9606 22393468 t llicata Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo SIGNOR-196397 0.2 ITCH protein Q96J02 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29685903 t miannu Mechanistically, Itch ubiquitinates Foxo1 for proteasomal degradation. SIGNOR-278698 0.258 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. SIGNOR-133544 0.62 PKA proteinfamily SIGNOR-PF17 SIGNOR CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser40 PKRRRASsLSRDAER 27149373 t lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. SIGNOR-275631 0.2 FPR1 protein P21462 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥