GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q03181	P28702	2	binding	up-regulates	0.555	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105451
O75143	O75385	0	phosphorylation	up-regulates	0.917	Ulks directly phosphorylate atg13	SIGNOR-183957
P45983	O75581	1	phosphorylation	up-regulates	0.382	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-169007
Q13568	P07948	0	phosphorylation	down-regulates activity	0.329	Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity.	SIGNOR-277247
P08047	P68104	2	binding	up-regulates activity	0.2	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
O14640	Q9UP38	2	binding	up-regulates activity	0.688	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
Q9HBE4	Q9HBE5	2	binding	up-regulates	0.901	Il-21 mediates its biological effects via the il-21r in conjunction with the common receptor gamma-chain that is also shared by members of the il-2 family	SIGNOR-143849
P31749	Q96KG9	1	phosphorylation	up-regulates activity	0.255	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
Q8IVF5	Q15835	0	phosphorylation	down-regulates activity	0.2	For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ).	SIGNOR-279997
Q16539	Q9UEW8	2	binding	up-regulates	0.362	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
P09651	P31749	0	phosphorylation	down-regulates	0.412	Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.	SIGNOR-252519
P43403	Q9UQQ2	1	phosphorylation	up-regulates	0.363	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
Q7Z569	Q7Z569	2	ubiquitination	down-regulates quantity by destabilization	0.2	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.	SIGNOR-272027
Q9H2K2	P54274	1	ADP-ribosylation	down-regulates activity	0.549	Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres.	SIGNOR-263376
Q9UKB1	Q13485	1	ubiquitination	up-regulates	0.2	We have identified scf(beta-trcp1), a ubiquitin (e3) ligase, as a critical determinant for the protein degradation of smad4 protein.	SIGNOR-123060
Q03112	P62136	0	dephosphorylation	down-regulates activity	0.2	We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation.	SIGNOR-273430
Q9UPW6	P43354	1	transcriptional regulation	down-regulates quantity	0.295	Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development	SIGNOR-268930
P68400	P41236	1	phosphorylation	up-regulates activity	0.307	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
P15173	Q969P5	2	binding	down-regulates activity	0.512	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
P0DMV8	Q9HC98	0	phosphorylation	up-regulates activity	0.425	Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.	SIGNOR-273885
P12931	O60716	1	phosphorylation	up-regulates activity	0.922	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-246484
Q70Z35	P62136	0	dephosphorylation	up-regulates activity	0.2	PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.	SIGNOR-277183
P34896	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.276	Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis	SIGNOR-267379
P29590	P28482	0	phosphorylation	up-regulates	0.359	We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis.	SIGNOR-124248
Q12834	P14635	2	binding	down-regulates quantity by destabilization	0.968	These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells.	SIGNOR-272578
A8K4G0	P62993	2	binding	up-regulates activity	0.462	The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2.	SIGNOR-264833
Q9BYX4	Q6PJ69	0	ubiquitination	up-regulates activity	0.448	These results indicate that TRIM65 promotes MDA5 ubiquitination at lysine 743, which is important for MDA5 activation.	SIGNOR-278535
P78527	P11387	1	phosphorylation	down-regulates quantity by destabilization	0.448	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
P26038	Q13464	0	phosphorylation	up-regulates activity	0.688	Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes.	SIGNOR-249014
Q8WY64	Q14114	1	ubiquitination	down-regulates quantity by destabilization	0.444	Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.	SIGNOR-271486
Q8N2H9	Q9Y4K3	1	ubiquitination	down-regulates quantity	0.63	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
O60674	P27361	0	phosphorylation	down-regulates	0.523	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-146747
P84022	Q06710	2	binding	down-regulates activity	0.366	DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-Î² decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3.	SIGNOR-251992
Q13188	Q7L7X3	0	phosphorylation	up-regulates	0.298	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-201321
P13501	P51677	2	binding	up-regulates	0.768	In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5	SIGNOR-254370
Q06124	Q9UQC2	1	dephosphorylation	down-regulates	0.742	Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.	SIGNOR-124958
P60953	Q13177	2	binding	up-regulates activity	0.885	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248253
P49841	Q05513	0	phosphorylation	down-regulates	0.597	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
P50406	Q14344	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257443
Q99878	Q86Y13	0	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271762
P00533	P35790	2	binding	up-regulates activity	0.401	We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines	SIGNOR-266352
Q13467	P41221	2	binding	up-regulates	0.832	These results identify hfz5 as a receptor for wnt-5a.	SIGNOR-46897
P28336	P38405	2	binding	up-regulates activity	0.278	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256918
P04628	Q8N474	2	binding	down-regulates	0.784	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
P68431	O14965	0	phosphorylation	up-regulates activity	0.2	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
P07384	P49840	1	cleavage	up-regulates activity	0.2	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251585
P67775	P05771-2	1	dephosphorylation	down-regulates activity	0.446	Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform	SIGNOR-248621
Q9UER7	P37173	2	binding	up-regulates	0.528	Tgf-beta-induced apoptosis is mediated by the adapter protein daxx that facilitates jnk activation	SIGNOR-109542
Q92833	P43694	2	binding	down-regulates activity	0.456	JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.	SIGNOR-224697
Q86X55	P40925	1	acetylation	down-regulates activity	0.355	Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer\|Arginine methylation at R248 negatively regulates MDH1 activity\|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization	SIGNOR-267639
P19484	Q00534	0	phosphorylation	up-regulates activity	0.2	CDK4 and CDK6 phosphorylate TFEB and TFE3.	SIGNOR-279454
P55011	Q9UEW8	0	phosphorylation	up-regulates activity	0.6	This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1	SIGNOR-264642
P14923	P16591	0	phosphorylation	up-regulates activity	0.526	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
Q13671	Q13129	2	binding	up-regulates activity	0.2	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
P04637	O15392	2	binding	down-regulates	0.562	This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest.	SIGNOR-111971
P29353	P43403	0	phosphorylation	up-regulates	0.677	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
Q9P253	P62837	2	binding	up-regulates activity	0.32	VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.	SIGNOR-271549
Q8WWG1	Q15303	2	binding	up-regulates	0.696	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
P22455	P22455	2	phosphorylation	up-regulates	0.2	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
O00571	P35637	0	relocalization	down-regulates activity	0.256	We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.\|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. \| We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons	SIGNOR-262811
Q9UIK4	Q8N122	1	phosphorylation	down-regulates activity	0.354	DAPK2 phosphorylates raptor in vitro on Ser721.	SIGNOR-278243
Q9NR28	Q16611	0	relocalization	up-regulates	0.522	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-118905
P02810	P48730	0	phosphorylation	up-regulates	0.2	Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22	SIGNOR-75272
Q8IWA4	P05771	0	phosphorylation	down-regulates activity	0.2	Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure.	SIGNOR-273826
P68400	Q9UJU2	1	phosphorylation	up-regulates	0.303	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
Q03135	P54762	0	phosphorylation	down-regulates quantity by destabilization	0.2	EphB1-dependent Y-14 phosphorylation of Cav-1 regulates caveolae endocytosis and endothelial permeability.	SIGNOR-280008
P14416	P30559	2	binding	up-regulates activity	0.374	Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling.	SIGNOR-270333
P40189	Q05655	0	phosphorylation	up-regulates activity	0.334	Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.	SIGNOR-249177
Q13309	Q5VWQ8	1	ubiquitination	down-regulates quantity by destabilization	0.267	DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1	SIGNOR-254775
Q9UNK0	Q5T447	0	polyubiquitination	down-regulates quantity by destabilization	0.44	Our co-immunoprecipitation experiments show that Syntaxin 8 directly interacts with HECTd3 and that the overexpression of HECTd3 promotes the ubiquitination of Syntaxin 8. Immunoprecipitates probed with the anti-ubiquitin (Santa Cruz) antibody could be recognized by the anti-ubiquin antibody (Fig. 3a), indicating that the shift of the His-syntaxin 8 protein bands were caused by polyubiquitin conjugations. Our data suggest that HECTd3 may function as an E3 ubiquitin-protein ligase to promote the ubiquitination and degradation of Syntaxin 8 through the proteasome pathway.	SIGNOR-271772
O95837	Q8TDV5	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257415
O43524	O75874	1	transcriptional regulation	up-regulates quantity by expression	0.248	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260100
P38405	P07550	2	binding	up-regulates activity	0.425	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data 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
P67870	Q13698	1	phosphorylation	up-regulates activity	0.2	To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.	SIGNOR-263115
O60496	P23470	0	dephosphorylation	up-regulates activity	0.2	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254698
O14672	P16070	1	cleavage	up-regulates activity	0.346	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.	SIGNOR-259847
P28482	P17535	1	phosphorylation	up-regulates	0.529	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196030
P03372	P24941	0	phosphorylation	up-regulates	0.477	The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha	SIGNOR-200867
Q13761	P11802	0	phosphorylation	down-regulates	0.399	Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.	SIGNOR-185120
P51955	Q9BV73	1	phosphorylation	down-regulates	0.774	C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.	SIGNOR-204837
O15379	P05091	2	binding	up-regulates activity	0.2	Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.\|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2.	SIGNOR-271867
Q92730	Q14451	2	binding	up-regulates	0.592	We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo.	SIGNOR-74914
Q13144	P41091	1	guanine nucleotide exchange factor	up-regulates activity	0.735	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269133
P02647	Q99523	2	binding	up-regulates quantity	0.331	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
P06493	Q15942	1	phosphorylation	up-regulates activity	0.309	As predicted by our hypothesis, the Cdc2 dependent phosphorylation has been shown to allow the full-length zyxin to interact with h-warts and LATS1 (XREF_FIG A).\|Phosphorylation of Zyxin by Cdc2 Regulates Binding to h-warts and LATS1.	SIGNOR-279498
Q9H9Z2	P01344	1	translation regulation	up-regulates quantity by expression	0.397	Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency	SIGNOR-277339
P06493	Q8WUX9	1	phosphorylation	down-regulates activity	0.2	We found that recombinant CHMP7 could be directly phosphorylated by CDK1/CCNB1 in vitro and that CDK1-phosphorylation reduced the capacity of CHMP7 to sediment (Figure 4A and B).\|We identified direct CDK1 phosphorylation of CHMP7 at Ser3 and Ser441 as a suppressor of both CHMP7\u2019s ability to interact with LEM2 and its ability to assemble, as judged by sedimentation assays.	SIGNOR-279445
P06748	P31749	0	phosphorylation	down-regulates activity	0.534	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
O43175	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin.	SIGNOR-269075
Q6PHR2	P10071	1	phosphorylation	up-regulates activity	0.561	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro	SIGNOR-260799
P49841	Q9UKT6	1	phosphorylation	up-regulates activity	0.2	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-264851
P78527	Q92831	1	phosphorylation	up-regulates activity	0.417	In response to UV-induced DNA damage, DNA-PK phosphorylates and activates PCAF, and activated PCAF is transferred to photo lesion sites and further acetylates RPA1 at K163.	SIGNOR-280092
Q09013	P26678	1	phosphorylation	up-regulates	0.54	Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro	SIGNOR-131371
P30989	Q14344	2	binding	up-regulates activity	0.25	Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways	SIGNOR-278060
Q02078	Q00535	0	phosphorylation	down-regulates activity	0.506	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
Q6P1N0	P06493	0	phosphorylation	up-regulates activity	0.2	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
O14543	P52333	2	binding	down-regulates activity	0.699	SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).	SIGNOR-238645
Q9NY33	Q14145	1	cleavage	down-regulates quantity by destabilization	0.599	The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome	SIGNOR-268464
P35580	Q05513	0	phosphorylation	down-regulates	0.269	After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell	SIGNOR-146100
P12931	Q06187	1	phosphorylation	up-regulates activity	0.529	This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation.	SIGNOR-251100

Q03181

P28702

2

binding

up-regulates

0.555

Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology

SIGNOR-105451

O75143

O75385

0

phosphorylation

up-regulates

0.917

Ulks directly phosphorylate atg13

SIGNOR-183957

P45983

O75581

1

phosphorylation

up-regulates

0.382

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-169007

Q13568

P07948

0

phosphorylation

down-regulates activity

0.329

Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity.

SIGNOR-277247

P08047

P68104

2

binding

up-regulates activity

0.2

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

O14640

Q9UP38

2

binding

up-regulates activity

0.688

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

Q9HBE4

Q9HBE5

2

binding

up-regulates

0.901

Il-21 mediates its biological effects via the il-21r in conjunction with the common receptor gamma-chain that is also shared by members of the il-2 family

SIGNOR-143849

P31749

Q96KG9

1

phosphorylation

up-regulates activity

0.255

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

Q8IVF5

Q15835

0

phosphorylation

down-regulates activity

0.2

For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ).

SIGNOR-279997

Q16539

Q9UEW8

2

binding

up-regulates

0.362

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

P09651

P31749

0

phosphorylation

down-regulates

0.412

Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.

SIGNOR-252519

P43403

Q9UQQ2

1

phosphorylation

up-regulates

0.363

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

Q7Z569

2

ubiquitination

down-regulates quantity by destabilization

0.2

Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.

SIGNOR-272027

Q9H2K2

P54274

1

ADP-ribosylation

down-regulates activity

0.549

Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres.

SIGNOR-263376

Q9UKB1

Q13485

1

ubiquitination

up-regulates

0.2

We have identified scf(beta-trcp1), a ubiquitin (e3) ligase, as a critical determinant for the protein degradation of smad4 protein.

SIGNOR-123060

Q03112

P62136

0

dephosphorylation

down-regulates activity

0.2

We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation.

SIGNOR-273430

Q9UPW6

P43354

1

transcriptional regulation

down-regulates quantity

0.295

Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development

SIGNOR-268930

P68400

P41236

1

phosphorylation

up-regulates activity

0.307

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

P15173

Q969P5

2

binding

down-regulates activity

0.512

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

P0DMV8

Q9HC98

0

phosphorylation

up-regulates activity

0.425

Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.

SIGNOR-273885

P12931

O60716

1

phosphorylation

up-regulates activity

0.922

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-246484

Q70Z35

P62136

0

dephosphorylation

up-regulates activity

0.2

PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.

SIGNOR-277183

P34896

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.276

Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis

SIGNOR-267379

P29590

P28482

0

phosphorylation

up-regulates

0.359

We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis.

SIGNOR-124248

Q12834

P14635

2

binding

down-regulates quantity by destabilization

0.968

These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells.

SIGNOR-272578

A8K4G0

P62993

2

binding

up-regulates activity

0.462

The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2.

SIGNOR-264833

Q9BYX4

Q6PJ69

0

ubiquitination

up-regulates activity

0.448

These results indicate that TRIM65 promotes MDA5 ubiquitination at lysine 743, which is important for MDA5 activation.

SIGNOR-278535

P78527

P11387

1

phosphorylation

down-regulates quantity by destabilization

0.448

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

P26038

Q13464

0

phosphorylation

up-regulates activity

0.688

Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes.

SIGNOR-249014

Q8WY64

Q14114

1

ubiquitination

down-regulates quantity by destabilization

0.444

Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.

SIGNOR-271486

Q8N2H9

Q9Y4K3

1

ubiquitination

down-regulates quantity

0.63

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

O60674

P27361

0

phosphorylation

down-regulates

0.523

We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner

SIGNOR-146747

P84022

Q06710

2

binding

down-regulates activity

0.366

DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-Î² decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3.

SIGNOR-251992

Q13188

Q7L7X3

0

phosphorylation

up-regulates

0.298

In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.

SIGNOR-201321

P13501

P51677

2

binding

up-regulates

0.768

In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5

SIGNOR-254370

Q06124

Q9UQC2

1

dephosphorylation

down-regulates

0.742

Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.

SIGNOR-124958

P60953

Q13177

2

binding

up-regulates activity

0.885

A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.

SIGNOR-248253

P49841

Q05513

0

phosphorylation

down-regulates

0.597

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

P50406

Q14344

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257443

Q99878

Q86Y13

0

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271762

P00533

P35790

2

binding

up-regulates activity

0.401

We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines

SIGNOR-266352

Q13467

P41221

2

binding

up-regulates

0.832

These results identify hfz5 as a receptor for wnt-5a.

SIGNOR-46897

P28336

P38405

2

binding

up-regulates activity

0.278

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256918

P04628

Q8N474

2

binding

down-regulates

0.784

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

P68431

O14965

0

phosphorylation

up-regulates activity

0.2

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

P07384

P49840

1

cleavage

up-regulates activity

0.2

Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase

SIGNOR-251585

P67775

P05771-2

1

dephosphorylation

down-regulates activity

0.446

Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform

SIGNOR-248621

Q9UER7

P37173

2

binding

up-regulates

0.528

Tgf-beta-induced apoptosis is mediated by the adapter protein daxx that facilitates jnk activation

SIGNOR-109542

Q92833

P43694

2

binding

down-regulates activity

0.456

JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.

SIGNOR-224697

Q86X55

P40925

1

acetylation

down-regulates activity

0.355

Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization

SIGNOR-267639

P19484

Q00534

0

phosphorylation

up-regulates activity

0.2

CDK4 and CDK6 phosphorylate TFEB and TFE3.

SIGNOR-279454

P55011

Q9UEW8

0

phosphorylation

up-regulates activity

0.6

This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1

SIGNOR-264642

P14923

P16591

0

phosphorylation

up-regulates activity

0.526

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

Q13671

Q13129

2

binding

up-regulates activity

0.2

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

P04637

O15392

2

binding

down-regulates

0.562

This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest.

SIGNOR-111971

P29353

P43403

0

phosphorylation

up-regulates

0.677

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

Q9P253

P62837

2

binding

up-regulates activity

0.32

VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.

SIGNOR-271549

Q8WWG1

Q15303

2

binding

up-regulates

0.696

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

P22455

2

phosphorylation

up-regulates

0.2

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

O00571

P35637

0

relocalization

down-regulates activity

0.256

We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons

SIGNOR-262811

Q9UIK4

Q8N122

1

phosphorylation

down-regulates activity

0.354

DAPK2 phosphorylates raptor in vitro on Ser721.

SIGNOR-278243

Q9NR28

Q16611

0

relocalization

up-regulates

0.522

Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi

SIGNOR-118905

P02810

P48730

0

phosphorylation

up-regulates

0.2

Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22

SIGNOR-75272

Q8IWA4

P05771

0

phosphorylation

down-regulates activity

0.2

Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure.

SIGNOR-273826

P68400

Q9UJU2

1

phosphorylation

up-regulates

0.303

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

Q03135

P54762

0

phosphorylation

down-regulates quantity by destabilization

0.2

EphB1-dependent Y-14 phosphorylation of Cav-1 regulates caveolae endocytosis and endothelial permeability.

SIGNOR-280008

P14416

P30559

2

binding

up-regulates activity

0.374

Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling.

SIGNOR-270333

P40189

Q05655

0

phosphorylation

up-regulates activity

0.334

Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.

SIGNOR-249177

Q13309

Q5VWQ8

1

ubiquitination

down-regulates quantity by destabilization

0.267

DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1

SIGNOR-254775

Q9UNK0

Q5T447

0

polyubiquitination

down-regulates quantity by destabilization

0.44

Our co-immunoprecipitation experiments show that Syntaxin 8 directly interacts with HECTd3 and that the overexpression of HECTd3 promotes the ubiquitination of Syntaxin 8. Immunoprecipitates probed with the anti-ubiquitin (Santa Cruz) antibody could be recognized by the anti-ubiquin antibody (Fig. 3a), indicating that the shift of the His-syntaxin 8 protein bands were caused by polyubiquitin conjugations. Our data suggest that HECTd3 may function as an E3 ubiquitin-protein ligase to promote the ubiquitination and degradation of Syntaxin 8 through the proteasome pathway.

SIGNOR-271772

O95837

Q8TDV5

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257415

O43524

O75874

1

transcriptional regulation

up-regulates quantity by expression

0.248

We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.

SIGNOR-260100

P38405

P07550

2

binding

up-regulates activity

0.425

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data 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

P67870

Q13698

1

phosphorylation

up-regulates activity

0.2

To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.

SIGNOR-263115

O60496

P23470

0

dephosphorylation

up-regulates activity

0.2

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254698

O14672

P16070

1

cleavage

up-regulates activity

0.346

The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.

SIGNOR-259847

P28482

P17535

1

phosphorylation

up-regulates

0.529

Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.

SIGNOR-196030

P03372

P24941

0

phosphorylation

up-regulates

0.477

The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha

SIGNOR-200867

Q13761

P11802

0

phosphorylation

down-regulates

0.399

Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.

SIGNOR-185120

P51955

Q9BV73

1

phosphorylation

down-regulates

0.774

C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.

SIGNOR-204837

O15379

P05091

2

binding

up-regulates activity

0.2

Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2.

SIGNOR-271867

Q92730

Q14451

2

binding

up-regulates

0.592

We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo.

SIGNOR-74914

Q13144

P41091

1

guanine nucleotide exchange factor

up-regulates activity

0.735

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269133

P02647

Q99523

2

binding

up-regulates quantity

0.331

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

P06493

Q15942

1

phosphorylation

up-regulates activity

0.309

As predicted by our hypothesis, the Cdc2 dependent phosphorylation has been shown to allow the full-length zyxin to interact with h-warts and LATS1 (XREF_FIG A).|Phosphorylation of Zyxin by Cdc2 Regulates Binding to h-warts and LATS1.

SIGNOR-279498

Q9H9Z2

P01344

1

translation regulation

up-regulates quantity by expression

0.397

Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency

SIGNOR-277339

P06493

Q8WUX9

1

phosphorylation

down-regulates activity

0.2

We found that recombinant CHMP7 could be directly phosphorylated by CDK1/CCNB1 in vitro and that CDK1-phosphorylation reduced the capacity of CHMP7 to sediment (Figure 4A and B).|We identified direct CDK1 phosphorylation of CHMP7 at Ser3 and Ser441 as a suppressor of both CHMP7\u2019s ability to interact with LEM2 and its ability to assemble, as judged by sedimentation assays.

SIGNOR-279445

P06748

P31749

0

phosphorylation

down-regulates activity

0.534

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

O43175

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin.

SIGNOR-269075

Q6PHR2

P10071

1

phosphorylation

up-regulates activity

0.561

We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro

SIGNOR-260799

P49841

Q9UKT6

1

phosphorylation

up-regulates activity

0.2

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-264851

P78527

Q92831

1

phosphorylation

up-regulates activity

0.417

In response to UV-induced DNA damage, DNA-PK phosphorylates and activates PCAF, and activated PCAF is transferred to photo lesion sites and further acetylates RPA1 at K163.

SIGNOR-280092

Q09013

P26678

1

phosphorylation

up-regulates

0.54

Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro

SIGNOR-131371

P30989

Q14344

2

binding

up-regulates activity

0.25

Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways

SIGNOR-278060

Q02078

Q00535

0

phosphorylation

down-regulates activity

0.506

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

Q6P1N0

P06493

0

phosphorylation

up-regulates activity

0.2

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

O14543

P52333

2

binding

down-regulates activity

0.699

SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).

SIGNOR-238645

Q9NY33

Q14145

1

cleavage

down-regulates quantity by destabilization

0.599

The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome

SIGNOR-268464

P35580

Q05513

0

phosphorylation

down-regulates

0.269

After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell

SIGNOR-146100

P12931

Q06187

1

phosphorylation

up-regulates activity

0.529

This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation.

SIGNOR-251100