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
Q9Y2X9	Q9UKB1	0	ubiquitination	down-regulates quantity by destabilization	0.2	E3 ligase the beta-transducin repeat-containing protein 2 (beta-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous beta-TrCP2 were inversely correlated with ZNF281.	SIGNOR-264897
Q13153	Q7L099	1	phosphorylation	up-regulates quantity	0.277	(a) PAK1 phosphorylates RUFY3 in vitro.\|Taken together, these results indicate that PAK1 can upregulate RUFY3 protein expression.	SIGNOR-279243
P61224	P17612	0	phosphorylation	up-regulates	0.522	These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation	SIGNOR-187410
Q14457	P53355	0	phosphorylation	up-regulates	0.727	The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.	SIGNOR-183548
P18031	P31749	2	dephosphorylation	down-regulates	0.742	Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs	SIGNOR-252639
P12036	P28482	0	phosphorylation	up-regulates activity	0.368	The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. \|Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation.	SIGNOR-249424
P07814	P18848	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269419
P35052	O75093	2	binding	up-regulates	0.382	Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis.	SIGNOR-68327
P15172	Q99623	2	binding	down-regulates	0.365	Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation.	SIGNOR-235843
Q15398	Q9Y566	1	relocalization	up-regulates activity	0.448	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264598
Q8N5S9	Q8IU85	1	phosphorylation	up-regulates activity	0.416	CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. \| This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells.	SIGNOR-250715
P51582	P19086	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257122
Q07812	P99999	1	relocalization	up-regulates	0.699	The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease	SIGNOR-73898
Q9Y5K6	A6ND36	2	binding	up-regulates activity	0.346	PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae\|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration.	SIGNOR-264768
P21554	O95837	2	binding	up-regulates activity	0.262	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257211
P24941	Q99626	1	phosphorylation	down-regulates quantity by destabilization	0.476	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation\|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.	SIGNOR-250729
P15260	P23458	2	binding	up-regulates	0.703	Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively	SIGNOR-150194
Q9Y6Q6	Q9Y4K3	2	binding	up-regulates activity	0.729	TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation.	SIGNOR-253045
P43405	P14317	1	phosphorylation	up-regulates	0.667	Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.	SIGNOR-47342
P29597	P51452	1	phosphorylation	up-regulates	0.265	Phosphorylation of vhr at tyr(138) was required for its phosphatase activity toward stat5. In addition, the src homology 2 domain of stat5 was required for the effective dephosphorylation of stat5 by vhr. The tyrosine kinase tyk2, which mediates the phosphorylation of stat5, was also responsible for the phosphorylation of vhr at tyr(138).	SIGNOR-157655
P43405	P31995	1	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-262675
Q8TB45	P43405	0	phosphorylation	down-regulates activity	0.2	We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner.	SIGNOR-277572
Q6N021	P19544	2	binding	up-regulates activity	0.447	In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes.	SIGNOR-255703
O43307	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.834	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260534
P42684	P07203	1	phosphorylation	up-regulates activity	0.322	GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.	SIGNOR-104328
P06213	O14492	2	binding	down-regulates	0.621	APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor.	SIGNOR-109694
Q6PCD5	P04637	1	ubiquitination	up-regulates quantity by stabilization	0.361	RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.	SIGNOR-271944
Q07817	Q9H4B4	0	phosphorylation	up-regulates	0.391	Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest.	SIGNOR-172230
Q86UE8	Q9Y294	1	phosphorylation	up-regulates quantity by stabilization	0.668	We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 \| Consistent	SIGNOR-260787
Q4KMG0	P55291	2	binding	up-regulates activity	0.499	Cdo binds promyogenic cadherins form complexes with n- and m-cadherin.	SIGNOR-99250
Q12866	Q12866	2	phosphorylation	up-regulates	0.2	By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain.	SIGNOR-42914
P49674	O15169	1	phosphorylation	up-regulates	0.747	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms.	SIGNOR-87444
P25106	O14625	2	binding	up-regulates activity	0.637	This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11)	SIGNOR-268415
Q14145	Q96HS1	2	binding	down-regulates quantity by destabilization	0.552	Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex.	SIGNOR-272645
P09471	Q9UPC5	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256967
P12931	Q9UJM3	1	phosphorylation	down-regulates activity	0.414	Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.\|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395.	SIGNOR-279116
Q9HC29	P0DMV9	2	binding	up-regulates quantity by stabilization	0.2	The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease.	SIGNOR-252417
P09471	P28221	2	binding	up-regulates activity	0.375	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257000
P09769	P09769	2	phosphorylation	up-regulates activity	0.2	Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation	SIGNOR-251143
P55211	Q13489	2	binding	down-regulates	0.76	Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11	SIGNOR-56481
P37231	P11310	2	binding	down-regulates activity	0.346	This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation	SIGNOR-261264
Q16539	P28562	2	binding	up-regulates activity	0.805	Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase.	SIGNOR-83752
P51153	Q6UB99	0	transcriptional regulation	up-regulates quantity by expression	0.2	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.	SIGNOR-266738
Q15796	Q9NYA4	0	dephosphorylation	down-regulates	0.53	Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes.	SIGNOR-163031
P56817	P40818	0	deubiquitination	up-regulates quantity by stabilization	0.45	Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501.	SIGNOR-259101
O15169	P49841	0	phosphorylation	up-regulates activity	0.92	Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP	SIGNOR-251221
Q9P289	P35222	1	phosphorylation	up-regulates quantity by stabilization	0.2	In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates \u03b2-catenin at Thr40 to block its Ser33 phosphorylation by GSK3\u03b2.	SIGNOR-280141
A4D2P6	O43424	2	binding	up-regulates quantity	0.609	We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules.	SIGNOR-264475
P17252	P13569	1	phosphorylation	up-regulates activity	0.399	Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC.	SIGNOR-248849
P63279	O95243	1	sumoylation	up-regulates activity	0.2	MBD4 is sumoylated at three main sites: K137, K215 and K377.\|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.\|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275678
P14778	Q99836	2	binding	up-regulates activity	0.945	Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88.	SIGNOR-67140
P40818	Q9H4P4	2	deubiquitination	up-regulates quantity by stabilization	0.88	Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins.	SIGNOR-259105
Q05086	P48436	1	ubiquitination	down-regulates quantity by destabilization	0.261	We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes.	SIGNOR-272134
P42224	Q06124	0	dephosphorylation	down-regulates activity	0.743	SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei\|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) \|Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity.	SIGNOR-248673
P29034	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.318	S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.	SIGNOR-272918
Q9UNE7	P55036	1	polyubiquitination	down-regulates quantity by destabilization	0.421	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s.	SIGNOR-272752
Q38SD2	Q96SN8	1	phosphorylation	up-regulates activity	0.505	Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation.	SIGNOR-275468
Q9UNS1	O14757	2	binding	up-regulates activity	0.795	We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization.	SIGNOR-268054
Q32MZ4	P00533	1	transcriptional regulation	down-regulates quantity by repression	0.293	GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. \|Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter.	SIGNOR-266057
P31995	P43405	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-262675
Q9H765	O14920	2	ubiquitination	down-regulates quantity by destabilization	0.2	In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity.	SIGNOR-272253
O60674	P00533	1	phosphorylation	up-regulates activity	0.612	Tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR.¬†	SIGNOR-251347
Q13480	P42336	2	binding	up-regulates	0.452	We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1.	SIGNOR-83343
P17252	Q6UVK1	1	phosphorylation	up-regulates activity	0.2	Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility.	SIGNOR-263162
P10242	Q86Z02	0	phosphorylation	down-regulates activity	0.2	C-Myb appears to be phosphorylated by HIPK1 in its negative regulatory domain as supported by both in vivo and in vitro data.	SIGNOR-279189
Q5NUL3	P50148	2	binding	up-regulates activity	0.449	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257371
P08700	P26951	2	binding	up-regulates	0.888	The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation.	SIGNOR-111404
Q9H492	Q13501	2	binding	up-regulates	0.791	Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.	SIGNOR-156353
Q06413	P12882	1	transcriptional regulation	up-regulates quantity by expression	0.383	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238754
P12931	P11413	1	phosphorylation	up-regulates activity	0.274	Here, we show that tyrosine kinase c-Src interacts with and phosphorylates G6PD at Tyr 112. This phosphorylation enhances catalytic activity of G6PD by dramatically decreasing its Km value and increasing its Kcat value for substrate glucose-6-phosphate.	SIGNOR-277550
P52948	Q9HC98	0	phosphorylation	down-regulates activity	0.315	To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization	SIGNOR-273893
Q00535	P46527	1	phosphorylation	down-regulates activity	0.643	CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins (XREF_FIG).\|During neural stem cell differentiation, CDK5 can phosphorylate p27 at Thr187 and at Ser10, promoting neurite outgrowth as neurons differentiate .	SIGNOR-279681
Q86YT6	Q9BVV6	1	ubiquitination	down-regulates quantity by destabilization	0.2	Conversely, expression of active, but not inactive, Mib1 likewise drastically reduced the levels of centriolar Talpid3 (XREF_FIG).\|Mib1 promotes the poly-ubiquitylation of Talpid3, Cep131, and PCM1.	SIGNOR-278829
O14905	Q9NPG1	2	binding	up-regulates	0.623	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132111
O15550	P20719	1	transcriptional regulation	up-regulates quantity by expression	0.27	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260023
Q03113	Q96RI0	2	binding	up-regulates	0.485	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).	SIGNOR-196012
Q99801	P10275	2	transcriptional regulation	down-regulates quantity by repression	0.502	Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.	SIGNOR-251547
P29590	Q13164	0	phosphorylation	down-regulates activity	0.474	Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.\|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation.	SIGNOR-279074
Q13177	P01106	1	phosphorylation	down-regulates activity	0.649	Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo.	SIGNOR-278489
Q96GD4	Q9NP77	1	phosphorylation	down-regulates quantity by destabilization	0.254	Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72.	SIGNOR-275529
Q8N9N5	Q07666	2	binding	down-regulates activity	0.309	SMAR1 Interacts with Sam68 in a Signal-Dependent Manner. HDAC6 in complex with SMAR1 deacetylates Sam68. Here, we document that SMAR1, in cooperation with histone deacetylase 6 (HDAC6), interacts with Sam68 and maintains it in a deacetylated state, concomitantly inhibiting the inclusion of CD44 alternate exons.	SIGNOR-266201
P31749	O75376	1	phosphorylation	down-regulates	0.424	Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype.	SIGNOR-198913
P46934	P42261	1	ubiquitination	down-regulates quantity	0.419	Finally, we show that ubiquitination of GluA1 by Nedd4-1 becomes more prevalent as neurons mature.\|The ability of Nedd4-1 to reduce surface GluA1 levels required its ligase activity, since co-expression of a catalytically-inactive version of Nedd4-1 (Nedd4-1 CS) did not decrease surface GluA1 levels .	SIGNOR-278572
P42336	Q9Y4K3	0	ubiquitination	up-regulates activity	0.458	In contrast to NEDD4L, overexpression of TRAF6 increases the stability of PIK3CA protein and promotes PI3K activation.\|TRAF6 ubiquitinates PIK3CA in vivo.	SIGNOR-278727
Q3KR16	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.297	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260568
Q8IXL6	Q8NBP7	1	phosphorylation	up-regulates activity	0.537	Herein, we report that Fam20C and Fam20A significantly eliminate the Furin-cleavage of PCSK9 (XREF_FIG, lanes 5, 6), thereby enhancing the pPCSK9 activity\|Herein, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668 and 688.	SIGNOR-278935
P43405	P10636	1	phosphorylation	down-regulates	0.466	We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth.	SIGNOR-159648
Q13315	Q15109	1	phosphorylation	up-regulates activity	0.2	RAGE is phosphorylated at Serine 376 and Serine 389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response.	SIGNOR-278907
O00165	P16615	2	binding	down-regulates quantity by destabilization	0.37	The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.\|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels.	SIGNOR-262052
Q9UHD2	Q15025	1	phosphorylation	down-regulates quantity by destabilization	0.375	TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1	SIGNOR-275733
P31946	O14920	0	phosphorylation	down-regulates	0.37	We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm.	SIGNOR-138608
Q15067	Q9NXA8	0	catalytic activity	down-regulates activity	0.26	SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.	SIGNOR-261210
P63027	Q9ULU8	2	binding	up-regulates activity	0.428	CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.	SIGNOR-264340
Q13671	P01112	2	binding	up-regulates	0.636	We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.	SIGNOR-113967
Q5FWF5	O00311	0	phosphorylation	down-regulates	0.432	We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1.	SIGNOR-200397
P60484	P29375	0	transcriptional regulation	down-regulates quantity by destabilization	0.289	The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL.	SIGNOR-260079
Q9ULV8	P00533	1	polyubiquitination	down-regulates quantity by destabilization	0.761	In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.	SIGNOR-272605
Q6VVB1	P35573	1	ubiquitination	down-regulates quantity by destabilization	0.56	The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL.	SIGNOR-271669
P0DMV8	Q9UL15	2	binding	down-regulates activity	0.753	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.	SIGNOR-261196
Q8N103	P61586	1	gtpase-activating protein	down-regulates activity	0.447	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260523

Q9Y2X9

Q9UKB1

0

ubiquitination

down-regulates quantity by destabilization

0.2

E3 ligase the beta-transducin repeat-containing protein 2 (beta-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous beta-TrCP2 were inversely correlated with ZNF281.

SIGNOR-264897

Q13153

Q7L099

1

phosphorylation

up-regulates quantity

0.277

(a) PAK1 phosphorylates RUFY3 in vitro.|Taken together, these results indicate that PAK1 can upregulate RUFY3 protein expression.

SIGNOR-279243

P61224

P17612

0

phosphorylation

up-regulates

0.522

These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation

SIGNOR-187410

Q14457

P53355

0

phosphorylation

up-regulates

0.727

The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.

SIGNOR-183548

P18031

P31749

2

dephosphorylation

down-regulates

0.742

Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs

SIGNOR-252639

P12036

P28482

0

phosphorylation

up-regulates activity

0.368

The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation.

SIGNOR-249424

P07814

P18848

0

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269419

P35052

O75093

2

binding

up-regulates

0.382

Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis.

SIGNOR-68327

P15172

Q99623

2

binding

down-regulates

0.365

Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation.

SIGNOR-235843

Q15398

Q9Y566

1

relocalization

up-regulates activity

0.448

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264598

Q8N5S9

Q8IU85

1

phosphorylation

up-regulates activity

0.416

CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. | This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells.

SIGNOR-250715

P51582

P19086

2

binding

up-regulates activity

0.2

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

SIGNOR-257122

Q07812

P99999

1

relocalization

up-regulates

0.699

The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease

SIGNOR-73898

Q9Y5K6

A6ND36

2

binding

up-regulates activity

0.346

PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration.

SIGNOR-264768

P21554

O95837

2

binding

up-regulates activity

0.262

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

SIGNOR-257211

P24941

Q99626

1

phosphorylation

down-regulates quantity by destabilization

0.476

Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.

SIGNOR-250729

P15260

P23458

2

binding

up-regulates

0.703

Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively

SIGNOR-150194

Q9Y6Q6

Q9Y4K3

2

binding

up-regulates activity

0.729

TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation.

SIGNOR-253045

P43405

P14317

1

phosphorylation

up-regulates

0.667

Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.

SIGNOR-47342

P29597

P51452

1

phosphorylation

up-regulates

0.265

Phosphorylation of vhr at tyr(138) was required for its phosphatase activity toward stat5. In addition, the src homology 2 domain of stat5 was required for the effective dephosphorylation of stat5 by vhr. The tyrosine kinase tyk2, which mediates the phosphorylation of stat5, was also responsible for the phosphorylation of vhr at tyr(138).

SIGNOR-157655

P43405

P31995

1

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-262675

Q8TB45

P43405

0

phosphorylation

down-regulates activity

0.2

We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner.

SIGNOR-277572

Q6N021

P19544

2

binding

up-regulates activity

0.447

In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes.

SIGNOR-255703

O43307

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.834

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260534

P42684

P07203

1

phosphorylation

up-regulates activity

0.322

GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.

SIGNOR-104328

P06213

O14492

2

binding

down-regulates

0.621

APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor.

SIGNOR-109694

Q6PCD5

P04637

1

ubiquitination

up-regulates quantity by stabilization

0.361

RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.

SIGNOR-271944

Q07817

Q9H4B4

0

phosphorylation

up-regulates

0.391

Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest.

SIGNOR-172230

Q86UE8

Q9Y294

1

phosphorylation

up-regulates quantity by stabilization

0.668

We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | Consistent

SIGNOR-260787

Q4KMG0

P55291

2

binding

up-regulates activity

0.499

Cdo binds promyogenic cadherins form complexes with n- and m-cadherin.

SIGNOR-99250

Q12866

2

phosphorylation

up-regulates

0.2

By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain.

SIGNOR-42914

P49674

O15169

1

phosphorylation

up-regulates

0.747

We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms.

SIGNOR-87444

P25106

O14625

2

binding

up-regulates activity

0.637

This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11)

SIGNOR-268415

Q14145

Q96HS1

2

binding

down-regulates quantity by destabilization

0.552

Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex.

SIGNOR-272645

P09471

Q9UPC5

2

binding

up-regulates activity

0.2

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

SIGNOR-256967

P12931

Q9UJM3

1

phosphorylation

down-regulates activity

0.414

Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395.

SIGNOR-279116

Q9HC29

P0DMV9

2

binding

up-regulates quantity by stabilization

0.2

The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease.

SIGNOR-252417

P09471

P28221

2

binding

up-regulates activity

0.375

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

SIGNOR-257000

P09769

2

phosphorylation

up-regulates activity

0.2

Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation

SIGNOR-251143

P55211

Q13489

2

binding

down-regulates

0.76

Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11

SIGNOR-56481

P37231

P11310

2

binding

down-regulates activity

0.346

This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation

SIGNOR-261264

Q16539

P28562

2

binding

up-regulates activity

0.805

Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase.

SIGNOR-83752

P51153

Q6UB99

0

transcriptional regulation

up-regulates quantity by expression

0.2

Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.

SIGNOR-266738

Q15796

Q9NYA4

0

dephosphorylation

down-regulates

0.53

Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes.

SIGNOR-163031

P56817

P40818

0

deubiquitination

up-regulates quantity by stabilization

0.45

Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501.

SIGNOR-259101

O15169

P49841

0

phosphorylation

up-regulates activity

0.92

Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP

SIGNOR-251221

Q9P289

P35222

1

phosphorylation

up-regulates quantity by stabilization

0.2

In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates \u03b2-catenin at Thr40 to block its Ser33 phosphorylation by GSK3\u03b2.

SIGNOR-280141

A4D2P6

O43424

2

binding

up-regulates quantity

0.609

We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules.

SIGNOR-264475

P17252

P13569

1

phosphorylation

up-regulates activity

0.399

Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC.

SIGNOR-248849

P63279

O95243

1

sumoylation

up-regulates activity

0.2

MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.

SIGNOR-275678

P14778

Q99836

2

binding

up-regulates activity

0.945

Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88.

SIGNOR-67140

P40818

Q9H4P4

2

deubiquitination

up-regulates quantity by stabilization

0.88

Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins.

SIGNOR-259105

Q05086

P48436

1

ubiquitination

down-regulates quantity by destabilization

0.261

We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes.

SIGNOR-272134

P42224

Q06124

0

dephosphorylation

down-regulates activity

0.743

SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity.

SIGNOR-248673

P29034

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.318

S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.

SIGNOR-272918

Q9UNE7

P55036

1

polyubiquitination

down-regulates quantity by destabilization

0.421

S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s.

SIGNOR-272752

Q38SD2

Q96SN8

1

phosphorylation

up-regulates activity

0.505

Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation.

SIGNOR-275468

Q9UNS1

O14757

2

binding

up-regulates activity

0.795

We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization.

SIGNOR-268054

Q32MZ4

P00533

1

transcriptional regulation

down-regulates quantity by repression

0.293

GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. |Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter.

SIGNOR-266057

P31995

P43405

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-262675

Q9H765

O14920

2

ubiquitination

down-regulates quantity by destabilization

0.2

In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity.

SIGNOR-272253

O60674

P00533

1

phosphorylation

up-regulates activity

0.612

Tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR.¬†

SIGNOR-251347

Q13480

P42336

2

binding

up-regulates

0.452

We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1.

SIGNOR-83343

P17252

Q6UVK1

1

phosphorylation

up-regulates activity

0.2

Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility.

SIGNOR-263162

P10242

Q86Z02

0

phosphorylation

down-regulates activity

0.2

C-Myb appears to be phosphorylated by HIPK1 in its negative regulatory domain as supported by both in vivo and in vitro data.

SIGNOR-279189

Q5NUL3

P50148

2

binding

up-regulates activity

0.449

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

SIGNOR-257371

P08700

P26951

2

binding

up-regulates

0.888

The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation.

SIGNOR-111404

Q9H492

Q13501

2

binding

up-regulates

0.791

Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.

SIGNOR-156353

Q06413

P12882

1

transcriptional regulation

up-regulates quantity by expression

0.383

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238754

P12931

P11413

1

phosphorylation

up-regulates activity

0.274

Here, we show that tyrosine kinase c-Src interacts with and phosphorylates G6PD at Tyr 112. This phosphorylation enhances catalytic activity of G6PD by dramatically decreasing its Km value and increasing its Kcat value for substrate glucose-6-phosphate.

SIGNOR-277550

P52948

Q9HC98

0

phosphorylation

down-regulates activity

0.315

To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization

SIGNOR-273893

Q00535

P46527

1

phosphorylation

down-regulates activity

0.643

CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins (XREF_FIG).|During neural stem cell differentiation, CDK5 can phosphorylate p27 at Thr187 and at Ser10, promoting neurite outgrowth as neurons differentiate .

SIGNOR-279681

Q86YT6

Q9BVV6

1

ubiquitination

down-regulates quantity by destabilization

0.2

Conversely, expression of active, but not inactive, Mib1 likewise drastically reduced the levels of centriolar Talpid3 (XREF_FIG).|Mib1 promotes the poly-ubiquitylation of Talpid3, Cep131, and PCM1.

SIGNOR-278829

O14905

Q9NPG1

2

binding

up-regulates

0.623

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-132111

O15550

P20719

1

transcriptional regulation

up-regulates quantity by expression

0.27

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260023

Q03113

Q96RI0

2

binding

up-regulates

0.485

Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).

SIGNOR-196012

Q99801

P10275

2

transcriptional regulation

down-regulates quantity by repression

0.502

Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.

SIGNOR-251547

P29590

Q13164

0

phosphorylation

down-regulates activity

0.474

Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation.

SIGNOR-279074

Q13177

P01106

1

phosphorylation

down-regulates activity

0.649

Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo.

SIGNOR-278489

Q96GD4

Q9NP77

1

phosphorylation

down-regulates quantity by destabilization

0.254

Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72.

SIGNOR-275529

Q8N9N5

Q07666

2

binding

down-regulates activity

0.309

SMAR1 Interacts with Sam68 in a Signal-Dependent Manner. HDAC6 in complex with SMAR1 deacetylates Sam68. Here, we document that SMAR1, in cooperation with histone deacetylase 6 (HDAC6), interacts with Sam68 and maintains it in a deacetylated state, concomitantly inhibiting the inclusion of CD44 alternate exons.

SIGNOR-266201

P31749

O75376

1

phosphorylation

down-regulates

0.424

Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype.

SIGNOR-198913

P46934

P42261

1

ubiquitination

down-regulates quantity

0.419

Finally, we show that ubiquitination of GluA1 by Nedd4-1 becomes more prevalent as neurons mature.|The ability of Nedd4-1 to reduce surface GluA1 levels required its ligase activity, since co-expression of a catalytically-inactive version of Nedd4-1 (Nedd4-1 CS) did not decrease surface GluA1 levels .

SIGNOR-278572

P42336

Q9Y4K3

0

ubiquitination

up-regulates activity

0.458

In contrast to NEDD4L, overexpression of TRAF6 increases the stability of PIK3CA protein and promotes PI3K activation.|TRAF6 ubiquitinates PIK3CA in vivo.

SIGNOR-278727

Q3KR16

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.297

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260568

Q8IXL6

Q8NBP7

1

phosphorylation

up-regulates activity

0.537

Herein, we report that Fam20C and Fam20A significantly eliminate the Furin-cleavage of PCSK9 (XREF_FIG, lanes 5, 6), thereby enhancing the pPCSK9 activity|Herein, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668 and 688.

SIGNOR-278935

P43405

P10636

1

phosphorylation

down-regulates

0.466

We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth.

SIGNOR-159648

Q13315

Q15109

1

phosphorylation

up-regulates activity

0.2

RAGE is phosphorylated at Serine 376 and Serine 389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response.

SIGNOR-278907

O00165

P16615

2

binding

down-regulates quantity by destabilization

0.37

The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels.

SIGNOR-262052

Q9UHD2

Q15025

1

phosphorylation

down-regulates quantity by destabilization

0.375

TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1

SIGNOR-275733

P31946

O14920

0

phosphorylation

down-regulates

0.37

We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm.

SIGNOR-138608

Q15067

Q9NXA8

0

catalytic activity

down-regulates activity

0.26

SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.

SIGNOR-261210

P63027

Q9ULU8

2

binding

up-regulates activity

0.428

CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.

SIGNOR-264340

Q13671

P01112

2

binding

up-regulates

0.636

We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.

SIGNOR-113967

Q5FWF5

O00311

0

phosphorylation

down-regulates

0.432

We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1.

SIGNOR-200397

P60484

P29375

0

transcriptional regulation

down-regulates quantity by destabilization

0.289

The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL.

SIGNOR-260079

Q9ULV8

P00533

1

polyubiquitination

down-regulates quantity by destabilization

0.761

In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.

SIGNOR-272605

Q6VVB1

P35573

1

ubiquitination

down-regulates quantity by destabilization

0.56

The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL.

SIGNOR-271669

P0DMV8

Q9UL15

2

binding

down-regulates activity

0.753

Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.

SIGNOR-261196

Q8N103

P61586

1

gtpase-activating protein

down-regulates activity

0.447

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260523