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
Q9UNZ2	P07711	2	binding	down-regulates activity	0.2	The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L.	SIGNOR-265043
P48730	P04637	1	phosphorylation	up-regulates	0.578	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
Q9UNE7	Q99828	1	ubiquitination	down-regulates quantity	0.2	All those were suggesting that CHIP promotes CIB1 ubiquitination via the Lys 48 residue of ubiquitin.\|K10 and K65 were the Lysine (K) residues for CHIP mediated CIB1 degradation.	SIGNOR-278721
Q99683	Q14680	0	phosphorylation	up-regulates activity	0.271	MELK, as an upstream kinase of ASK1, phosphorylates threonine 838 in an activation loop of human ASK1, thereby stimulating ASK1 kinase activity.	SIGNOR-280039
P12931	P12931	2	phosphorylation	down-regulates activity	0.2	Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity	SIGNOR-43315
P35222	Q13308	2	binding	down-regulates	0.403	Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt.	SIGNOR-199536
P17302	P17252	0	phosphorylation	down-regulates	0.535	Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.	SIGNOR-120907
Q12923	P35568	1	dephosphorylation	down-regulates activity	0.466	Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.\|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo.	SIGNOR-277053
Q15118	P08559	1	phosphorylation	down-regulates activity	0.794	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109551
Q15078	P20807	0	cleavage	up-regulates activity	0.261	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-251604
Q96PV0	Q00535	0	phosphorylation	up-regulates activity	0.383	CDK5 increases recombinant SYNGAP1 activity on Ras-GAP by 98% and its Rap-GAP activity by 20%.\|Interestingly, phosphorylation of SYNGAP1 by CDK5 and CaMKII increases overall SYNGAP1 activity, but also alters the ratio of its GAP activity towards Ras- and Rap-GTPases.	SIGNOR-279157
O60885	Q96QE3	2	binding	up-regulates	0.35	ATAD5 Interacts with BRD4 through a Conserved BET Protein-Binding Domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin.	SIGNOR-266412
Q5JU85	P78352	1	relocalization	up-regulates activity	0.472	Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.	SIGNOR-264907
P49585	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.2	Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter	SIGNOR-266231
Q96BI3	Q92542	2	binding	up-regulates	0.967	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93259
Q13887	Q14258	0	polyubiquitination	down-regulates quantity by destabilization	0.482	The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked.	SIGNOR-271908
P00390	Q13131	0	phosphorylation	up-regulates activity	0.288	Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity.	SIGNOR-273734
P52655	P19784	0	phosphorylation	up-regulates activity	0.374	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
P09619	Q05397	1	phosphorylation	up-regulates	0.553	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167658
P41161	Q14938	0	transcriptional regulation	down-regulates quantity	0.2	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
P68400	Q92688	1	phosphorylation	up-regulates	0.234	Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna	SIGNOR-183158
O14920	Q16875	1	phosphorylation	down-regulates activity	0.29	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
Q9GZQ8	P19484	0	transcriptional regulation	up-regulates quantity by expression	0.391	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-276559
P35222	P46937	2	binding	up-regulates	0.531	Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue.	SIGNOR-201939
Q8N4X5	P42336	2	binding	up-regulates activity	0.2	RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha.	SIGNOR-263193
P41221	O75581	2	binding	up-regulates activity	0.758	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-131841
P07737	P61586	0	null	up-regulates activity	0.569	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.\|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.	SIGNOR-253109
P04637	P17844	2	binding	up-regulates	0.702	The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor	SIGNOR-133341
B2RTY4	P61586	1	gtpase-activating protein	down-regulates activity	0.565	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
P22694	Q92917	1	phosphorylation	up-regulates activity	0.307	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-266298
O75385	Q9C0C7	1	phosphorylation	up-regulates	0.695	When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation.	SIGNOR-168292
Q9Y4K3	O43474	1	ubiquitination	up-regulates quantity by stabilization	0.285	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-277464
Q8NFZ3	P58400	2	binding	up-regulates activity	0.2	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
P22612	Q14896	1	phosphorylation	up-regulates	0.275	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163788
P07948	P43405	1	phosphorylation	up-regulates activity	0.61	Lyn phosphorylates and activates Syk and LAT.	SIGNOR-279415
P28360	P20226	2	binding	down-regulates activity	0.397	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
O15350	P53350	0	phosphorylation	down-regulates	0.51	P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain.	SIGNOR-178253
P24071	P49840	0	phosphorylation	down-regulates activity	0.2	GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state.	SIGNOR-264856
Q9Y5I2	Q9Y5F6	2	binding	up-regulates activity	0.2	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
P63096	Q9GZQ4	2	binding	up-regulates activity	0.435	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data 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
Q96J02	P45983	0	phosphorylation	up-regulates activity	0.654	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-245323
P59594	Q9H2X3	2	binding	up-regulates activity	0.2	Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination.	SIGNOR-260269
P28482	Q07869	1	phosphorylation	up-regulates activity	0.578	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-249434
O60716	P22223	2	binding	up-regulates quantity by stabilization	0.751	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252124
P63244	Q5JWF2	2	binding	down-regulates activity	0.2	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
O43379	Q99759	2	relocalization	up-regulates activity	0.2	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271717
P19086	Q9Y5X5	2	binding	up-regulates activity	0.252	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257104
P49810	P68400	0	phosphorylation	up-regulates activity	0.307	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
P50613	P24928	1	phosphorylation	down-regulates	0.789	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-120024
O15379	P15976	0	relocalization	up-regulates activity	0.55	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-275664
Q9UH77	Q96J92	2	binding	down-regulates quantity by destabilization	0.585	Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein.	SIGNOR-272105
Q5JUK2	Q68G74	1	transcriptional regulation	up-regulates quantity by expression	0.486	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-266076
P17661	P06493	0	phosphorylation	down-regulates quantity by destabilization	0.2	In line with this, we found that in Drp/MC mice desmin was hyperphosphorylated in Ser-31 by a hyperactivated Cdk-1.	SIGNOR-278331
P36956	Q8WU17	0	ubiquitination	down-regulates quantity	0.298	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
P31995	P07948	0	phosphorylation	up-regulates activity	0.2	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
P49190	P01270	2	binding	up-regulates	0.7	Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor)	SIGNOR-115104
P21452	O95837	2	binding	up-regulates activity	0.433	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257131
P17612	Q9NXR1	1	phosphorylation	up-regulates	0.4	Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple	SIGNOR-174410
P53350	Q9BQQ3	1	phosphorylation	down-regulates quantity	0.729	As GRASP65 is a substrate of cdc2 and polo-like kinase, manipulation of GRASP65 level may affect the localization and activity of these kinases in cell cycle progression, as suggested by a previous study ( ).\|During mitosis, GRASP65 is phosphorylated by two mitotic kinases, cdc2 and polo-like kinase (plk), which leads to GRASP65 deoligomerization and thus Golgi unstacking ( xref , xref ).	SIGNOR-279554
P24941	P53350	1	phosphorylation	up-regulates activity	0.375	Thus, CycA2-CDK2 can stimulate phosphorylation of PLK1 T210 in vitro and the interactions required for CycA2-mediated PLK1 T210 phosphorylation are detected in the cytoplasm, but not in the nucleus.\|We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1.	SIGNOR-280212
P62820	Q08379	1	relocalization	up-regulates activity	0.718	Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi	SIGNOR-261285
P12931	P23467	0	dephosphorylation	down-regulates activity	0.445	Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.\|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2.	SIGNOR-277132
P10912	Q13163	1	phosphorylation	up-regulates activity	0.2	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion	SIGNOR-255452
Q14119	Q99967	1	transcriptional regulation	down-regulates quantity by repression	0.2	The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells	SIGNOR-266883
Q8TBB1	P22459	1	ubiquitination	down-regulates quantity by destabilization	0.283	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.The C-terminal LNX1 PDZ1-binding motifs of the ATP-binding cassette, subfamily A member 1 (ABC-1), PBK, glutamate receptor, ionotropic, N-methyl d-aspartate 1 (GRIN1), and Claudin-17 significantly promoted the ubiquitination of the corresponding artificial degrons by LNX1ΔPDZ234.	SIGNOR-272899
Q9UHB9	O76094	2	binding	up-regulates activity	0.99	Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction.	SIGNOR-261164
Q99496	Q6W2J9	2	binding	up-regulates activity	0.545	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
P04637	O60729	0	dephosphorylation	down-regulates activity	0.333	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
Q16143	P53350	0	phosphorylation	down-regulates activity	0.318	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-176079
P50539	Q9UQE7	2	binding	down-regulates activity	0.403	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 eects of Mad proteins on c-myc functions.	SIGNOR-241223
O15111	Q92985	1	phosphorylation	up-regulates	0.688	Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.	SIGNOR-146116
P52945	P13010	2	binding	down-regulates quantity by destabilization	0.307	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
P01106	Q92995	0	deubiquitination	up-regulates quantity by stabilization	0.353	In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation.	SIGNOR-274124
P09467	Q8IYT8	0	phosphorylation	down-regulates activity	0.2	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-274039
P63261	P29350	0	dephosphorylation	down-regulates	0.2	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
P68400	P30305	1	phosphorylation	up-regulates activity	0.338	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
P07949	Q8N4X5	1	phosphorylation	up-regulates activity	0.33	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
Q5JWF2	P43657	2	binding	up-regulates activity	0.323	LPAR1 is reported to associate with Gia,G12/13a,orGqa; LPAR3 with Gia or Gqa; and LPAR6 withGia,G12/13a,orGsa.	SIGNOR-278872
P27448	P11309	0	phosphorylation	down-regulates	0.418	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
Q9NR31	Q9NRC8	0	deacetylation	up-regulates activity	0.2	SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding	SIGNOR-260978
P57073	O14965	0	phosphorylation	up-regulates activity	0.2	Therefore, Aurora-A not only directly phosphorylates SOX8 but also promotes SOX8 transcription indirectly by regulating c-Myc protein.	SIGNOR-280189
Q9NZ42	Q96BI3	2	binding	up-regulates	0.962	Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97104
Q8N257	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	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
P40763	P45984	0	phosphorylation	up-regulates	0.482	Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.	SIGNOR-179275
Q9BPZ7	Q02156	2	binding	up-regulates activity	0.263	In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC.	SIGNOR-276348
P55211	P17612	0	phosphorylation	down-regulates	0.2	We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195.	SIGNOR-133884
Q6FI13	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-271755
Q14457	Q9NR19	0	transcriptional regulation	up-regulates quantity by expression	0.2	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-276561
P20827	P29317	2	binding	up-regulates	0.937	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm	SIGNOR-56901
O15554	Q9NRX4	0	dephosphorylation	down-regulates activity	0.549	We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1.\|Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity.	SIGNOR-277071
Q08999	O43524	0	transcriptional regulation	up-regulates quantity	0.291	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
P63096	Q9UKP6	2	binding	up-regulates activity	0.265	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257051
Q8N2Q7	P58401	2	binding	up-regulates activity	0.829	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264159
P54821	O60675	2	binding	down-regulates activity	0.273	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
Q7LBC6	P84243	1	demethylation	down-regulates activity	0.2	We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.	SIGNOR-266636
Q9UIJ5	P24588	1	palmitoylation	up-regulates activity	0.331	Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms	SIGNOR-261289
P41236	P62136	2	binding	down-regulates	0.785	Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1.	SIGNOR-160651
P48454	O00429	1	dephosphorylation	up-regulates activity	0.262	When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248506
Q96GD4	O96017	0	phosphorylation	up-regulates activity	0.324	Because Chk1 and Chk2 can share substrates ( ), we investigated whether Chk2 phosphorylates Aurora B-B-serine 331 in nocodazole.\|In addition, Chk2 promotes proper chromosome alignment through Aurora B-B-serine 331 phosphorylation.	SIGNOR-278906
P58753	O60603	2	binding	up-regulates activity	0.726	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266745

Q9UNZ2

P07711

2

binding

down-regulates activity

0.2

The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L.

SIGNOR-265043

P48730

P04637

1

phosphorylation

up-regulates

0.578

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

Q9UNE7

Q99828

1

ubiquitination

down-regulates quantity

0.2

All those were suggesting that CHIP promotes CIB1 ubiquitination via the Lys 48 residue of ubiquitin.|K10 and K65 were the Lysine (K) residues for CHIP mediated CIB1 degradation.

SIGNOR-278721

Q99683

Q14680

0

phosphorylation

up-regulates activity

0.271

MELK, as an upstream kinase of ASK1, phosphorylates threonine 838 in an activation loop of human ASK1, thereby stimulating ASK1 kinase activity.

SIGNOR-280039

P12931

2

phosphorylation

down-regulates activity

0.2

Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity

SIGNOR-43315

P35222

Q13308

2

binding

down-regulates

0.403

Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt.

SIGNOR-199536

P17302

P17252

0

phosphorylation

down-regulates

0.535

Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.

SIGNOR-120907

Q12923

P35568

1

dephosphorylation

down-regulates activity

0.466

Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo.

SIGNOR-277053

Q15118

P08559

1

phosphorylation

down-regulates activity

0.794

Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.

SIGNOR-109551

Q15078

P20807

0

cleavage

up-regulates activity

0.261

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-251604

Q96PV0

Q00535

0

phosphorylation

up-regulates activity

0.383

CDK5 increases recombinant SYNGAP1 activity on Ras-GAP by 98% and its Rap-GAP activity by 20%.|Interestingly, phosphorylation of SYNGAP1 by CDK5 and CaMKII increases overall SYNGAP1 activity, but also alters the ratio of its GAP activity towards Ras- and Rap-GTPases.

SIGNOR-279157

O60885

Q96QE3

2

binding

up-regulates

0.35

ATAD5 Interacts with BRD4 through a Conserved BET Protein-Binding Domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin.

SIGNOR-266412

Q5JU85

P78352

1

relocalization

up-regulates activity

0.472

Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.

SIGNOR-264907

P49585

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.2

Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter

SIGNOR-266231

Q96BI3

Q92542

2

binding

up-regulates

0.967

By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.

SIGNOR-93259

Q13887

Q14258

0

polyubiquitination

down-regulates quantity by destabilization

0.482

The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked.

SIGNOR-271908

P00390

Q13131

0

phosphorylation

up-regulates activity

0.288

Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity.

SIGNOR-273734

P52655

P19784

0

phosphorylation

up-regulates activity

0.374

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

P09619

Q05397

1

phosphorylation

up-regulates

0.553

In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.

SIGNOR-167658

P41161

Q14938

0

transcriptional regulation

down-regulates quantity

0.2

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

P68400

Q92688

1

phosphorylation

up-regulates

0.234

Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna

SIGNOR-183158

O14920

Q16875

1

phosphorylation

down-regulates activity

0.29

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

Q9GZQ8

P19484

0

transcriptional regulation

up-regulates quantity by expression

0.391

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-276559

P35222

P46937

2

binding

up-regulates

0.531

Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue.

SIGNOR-201939

Q8N4X5

P42336

2

binding

up-regulates activity

0.2

RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha.

SIGNOR-263193

P41221

O75581

2

binding

up-regulates activity

0.758

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-131841

P07737

P61586

0

null

up-regulates activity

0.569

We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.

SIGNOR-253109

P04637

P17844

2

binding

up-regulates

0.702

The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor

SIGNOR-133341

B2RTY4

P61586

1

gtpase-activating protein

down-regulates activity

0.565

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

P22694

Q92917

1

phosphorylation

up-regulates activity

0.307

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-266298

O75385

Q9C0C7

1

phosphorylation

up-regulates

0.695

When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation.

SIGNOR-168292

Q9Y4K3

O43474

1

ubiquitination

up-regulates quantity by stabilization

0.285

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-277464

Q8NFZ3

P58400

2

binding

up-regulates activity

0.2

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

P22612

Q14896

1

phosphorylation

up-regulates

0.275

Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).

SIGNOR-163788

P07948

P43405

1

phosphorylation

up-regulates activity

0.61

Lyn phosphorylates and activates Syk and LAT.

SIGNOR-279415

P28360

P20226

2

binding

down-regulates activity

0.397

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

O15350

P53350

0

phosphorylation

down-regulates

0.51

P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain.

SIGNOR-178253

P24071

P49840

0

phosphorylation

down-regulates activity

0.2

GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state.

SIGNOR-264856

Q9Y5I2

Q9Y5F6

2

binding

up-regulates activity

0.2

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

P63096

Q9GZQ4

2

binding

up-regulates activity

0.435

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

Q96J02

P45983

0

phosphorylation

up-regulates activity

0.654

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-245323

P59594

Q9H2X3

2

binding

up-regulates activity

0.2

Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination.

SIGNOR-260269

P28482

Q07869

1

phosphorylation

up-regulates activity

0.578

We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.

SIGNOR-249434

O60716

P22223

2

binding

up-regulates quantity by stabilization

0.751

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252124

P63244

Q5JWF2

2

binding

down-regulates activity

0.2

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

O43379

Q99759

2

relocalization

up-regulates activity

0.2

In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis

SIGNOR-271717

P19086

Q9Y5X5

2

binding

up-regulates activity

0.252

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

SIGNOR-257104

P49810

P68400

0

phosphorylation

up-regulates activity

0.307

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

P50613

P24928

1

phosphorylation

down-regulates

0.789

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-120024

O15379

P15976

0

relocalization

up-regulates activity

0.55

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-275664

Q9UH77

Q96J92

2

binding

down-regulates quantity by destabilization

0.585

Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein.

SIGNOR-272105

Q5JUK2

Q68G74

1

transcriptional regulation

up-regulates quantity by expression

0.486

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-266076

P17661

P06493

0

phosphorylation

down-regulates quantity by destabilization

0.2

In line with this, we found that in Drp/MC mice desmin was hyperphosphorylated in Ser-31 by a hyperactivated Cdk-1.

SIGNOR-278331

P36956

Q8WU17

0

ubiquitination

down-regulates quantity

0.298

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

P31995

P07948

0

phosphorylation

up-regulates activity

0.2

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

P49190

P01270

2

binding

up-regulates

0.7

Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor)

SIGNOR-115104

P21452

O95837

2

binding

up-regulates activity

0.433

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

SIGNOR-257131

P17612

Q9NXR1

1

phosphorylation

up-regulates

0.4

Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple

SIGNOR-174410

P53350

Q9BQQ3

1

phosphorylation

down-regulates quantity

0.729

As GRASP65 is a substrate of cdc2 and polo-like kinase, manipulation of GRASP65 level may affect the localization and activity of these kinases in cell cycle progression, as suggested by a previous study ( ).|During mitosis, GRASP65 is phosphorylated by two mitotic kinases, cdc2 and polo-like kinase (plk), which leads to GRASP65 deoligomerization and thus Golgi unstacking ( xref , xref ).

SIGNOR-279554

P24941

P53350

1

phosphorylation

up-regulates activity

0.375

Thus, CycA2-CDK2 can stimulate phosphorylation of PLK1 T210 in vitro and the interactions required for CycA2-mediated PLK1 T210 phosphorylation are detected in the cytoplasm, but not in the nucleus.|We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1.

SIGNOR-280212

P62820

Q08379

1

relocalization

up-regulates activity

0.718

Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi

SIGNOR-261285

P12931

P23467

0

dephosphorylation

down-regulates activity

0.445

Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2.

SIGNOR-277132

P10912

Q13163

1

phosphorylation

up-regulates activity

0.2

The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion

SIGNOR-255452

Q14119

Q99967

1

transcriptional regulation

down-regulates quantity by repression

0.2

The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells

SIGNOR-266883

Q8TBB1

P22459

1

ubiquitination

down-regulates quantity by destabilization

0.283

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.The C-terminal LNX1 PDZ1-binding motifs of the ATP-binding cassette, subfamily A member 1 (ABC-1), PBK, glutamate receptor, ionotropic, N-methyl d-aspartate 1 (GRIN1), and Claudin-17 significantly promoted the ubiquitination of the corresponding artificial degrons by LNX1ΔPDZ234.

SIGNOR-272899

Q9UHB9

O76094

2

binding

up-regulates activity

0.99

Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction.

SIGNOR-261164

Q99496

Q6W2J9

2

binding

up-regulates activity

0.545

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

P04637

O60729

0

dephosphorylation

down-regulates activity

0.333

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

Q16143

P53350

0

phosphorylation

down-regulates activity

0.318

Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.

SIGNOR-176079

P50539

Q9UQE7

2

binding

down-regulates activity

0.403

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 eects of Mad proteins on c-myc functions.

SIGNOR-241223

O15111

Q92985

1

phosphorylation

up-regulates

0.688

Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.

SIGNOR-146116

P52945

P13010

2

binding

down-regulates quantity by destabilization

0.307

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

P01106

Q92995

0

deubiquitination

up-regulates quantity by stabilization

0.353

In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation.

SIGNOR-274124

P09467

Q8IYT8

0

phosphorylation

down-regulates activity

0.2

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-274039

P63261

P29350

0

dephosphorylation

down-regulates

0.2

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

P68400

P30305

1

phosphorylation

up-regulates activity

0.338

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

P07949

Q8N4X5

1

phosphorylation

up-regulates activity

0.33

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

Q5JWF2

P43657

2

binding

up-regulates activity

0.323

LPAR1 is reported to associate with Gia,G12/13a,orGqa; LPAR3 with Gia or Gqa; and LPAR6 withGia,G12/13a,orGsa.

SIGNOR-278872

P27448

P11309

0

phosphorylation

down-regulates

0.418

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

Q9NR31

Q9NRC8

0

deacetylation

up-regulates activity

0.2

SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding

SIGNOR-260978

P57073

O14965

0

phosphorylation

up-regulates activity

0.2

Therefore, Aurora-A not only directly phosphorylates SOX8 but also promotes SOX8 transcription indirectly by regulating c-Myc protein.

SIGNOR-280189

Q9NZ42

Q96BI3

2

binding

up-regulates

0.962

Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.

SIGNOR-97104

Q8N257

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

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

P40763

P45984

0

phosphorylation

up-regulates

0.482

Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.

SIGNOR-179275

Q9BPZ7

Q02156

2

binding

up-regulates activity

0.263

In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC.

SIGNOR-276348

P55211

P17612

0

phosphorylation

down-regulates

0.2

We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195.

SIGNOR-133884

Q6FI13

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-271755

Q14457

Q9NR19

0

transcriptional regulation

up-regulates quantity by expression

0.2

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-276561

P20827

P29317

2

binding

up-regulates

0.937

Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm

SIGNOR-56901

O15554

Q9NRX4

0

dephosphorylation

down-regulates activity

0.549

We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1.|Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity.

SIGNOR-277071

Q08999

O43524

0

transcriptional regulation

up-regulates quantity

0.291

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

P63096

Q9UKP6

2

binding

up-regulates activity

0.265

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

SIGNOR-257051

Q8N2Q7

P58401

2

binding

up-regulates activity

0.829

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264159

P54821

O60675

2

binding

down-regulates activity

0.273

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

Q7LBC6

P84243

1

demethylation

down-regulates activity

0.2

We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.

SIGNOR-266636

Q9UIJ5

P24588

1

palmitoylation

up-regulates activity

0.331

Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms

SIGNOR-261289

P41236

P62136

2

binding

down-regulates

0.785

Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1.

SIGNOR-160651

P48454

O00429

1

dephosphorylation

up-regulates activity

0.262

When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.

SIGNOR-248506

Q96GD4

O96017

0

phosphorylation

up-regulates activity

0.324

Because Chk1 and Chk2 can share substrates ( ), we investigated whether Chk2 phosphorylates Aurora B-B-serine 331 in nocodazole.|In addition, Chk2 promotes proper chromosome alignment through Aurora B-B-serine 331 phosphorylation.

SIGNOR-278906

P58753

O60603

2

binding

up-regulates activity

0.726

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-266745