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
P22681	O94875	1	ubiquitination	down-regulates	0.512	Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl	SIGNOR-96325
Q92600	Q6Y7W6	2	binding	up-regulates activity	0.2	Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2	SIGNOR-260058
Q13315	Q9BW19	1	phosphorylation	up-regulates quantity by stabilization	0.2	ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.	SIGNOR-277295
O00755	O75581	2	binding	up-regulates activity	0.648	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-131903
Q9UBN4	Q96J02	0	ubiquitination	down-regulates activity	0.35	Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.	SIGNOR-272624
Q15831	Q7KZI7	1	phosphorylation	up-regulates activity	0.588	MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase.	SIGNOR-276165
Q16875	O14920	0	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
Q92888	P17252	0	phosphorylation	up-regulates activity	0.439	We showed that the first and second phase of RhoA activity are dependent on p63 and Ca2+/PKC, respectively, and further identified phosphorylation of serine 240 on p115 RhoGEF by PKC to be the mechanistic link between PKC and RhoA.	SIGNOR-277530
P09471	Q9HBW0	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257257
O75175	Q9Y6Q6	1	transcriptional regulation	down-regulates quantity by repression	0.2	Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis.	SIGNOR-261572
Q8TF76	P06493	0	phosphorylation	up-regulates activity	0.2	Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis.	SIGNOR-275419
Q16512	P10636	1	phosphorylation	down-regulates	0.329	Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly.	SIGNOR-84958
Q15038	Q9H2X6	0	phosphorylation	down-regulates activity	0.2	In response to DNA damage, HIPK2 phosphorylates DAZAP2 at several Ser/Thr residues including Ser77, which inhibits its HIPK2-degrading function and targets it to the cell nucleus.	SIGNOR-279335
Q9BXW4	Q14596	2	binding	down-regulates	0.53	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.	SIGNOR-184258
P05771	Q9H1D0	1	phosphorylation	down-regulates activity	0.2	This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload.	SIGNOR-276265
P29274	P19086	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257306
P13501	Q9BZS1	0	transcriptional regulation	up-regulates quantity by expression	0.434	Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression	SIGNOR-277727
Q9NQZ2	O00566	2	binding	up-regulates activity	0.934	Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome.	SIGNOR-261176
P24941	P30307	1	phosphorylation	up-regulates	0.754	The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.	SIGNOR-165872
P28482	Q86UC2	1	phosphorylation	up-regulates activity	0.2	ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). inhibiting ERK1/2 activity appears to negatively regulate the AKAP function of RSPH3.	SIGNOR-262839
Q14207	P24941	0	phosphorylation	up-regulates	0.447	Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.	SIGNOR-82141
Q99527	P50148	2	binding	up-regulates	0.2	However, grpr preferentially couples to galfaq proteins.	SIGNOR-195320
O15111	P06748	1	phosphorylation	up-regulates activity	0.2	S125A and a delta form lacking the aa 119-195 region completely abolished NPM phosphorylation by IKKalpha (XREF_FIG), suggesting that IKKalpha phosphorylates S125 of NPM.\|We found that TNFalpha treatment induced IKKalpha phosphorylation and increased NPM hexamers, which were correlated with increased NPM phosphorylation (XREF_FIG).	SIGNOR-279405
Q8N392	Q6P5Z2	0	phosphorylation	up-regulates activity	0.2	We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.\|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158.	SIGNOR-264572
P17612	Q13972	1	phosphorylation	up-regulates	0.519	Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors.	SIGNOR-73202
P29474	P0DP24	2	binding	up-regulates activity	0.505	Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer	SIGNOR-266323
P00533	P27986	2	binding	up-regulates	0.81	The egf-r coimmunoprecipitated with p85 alpha	SIGNOR-121959
P14859	Q9UKX2	1	transcriptional regulation	up-regulates quantity by expression	0.2	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-238757
P16949	P27361	0	phosphorylation	down-regulates activity	0.577	Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells\|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs.	SIGNOR-249483
P17612	P16070	1	phosphorylation	up-regulates	0.2	Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains.	SIGNOR-147208
Q15139	Q13936	1	phosphorylation	up-regulates	0.255	Both the expression of a dominant-negative mutant of pkd and the mutation of serine 1884 but not serine 1930, putative targets of pkd, strongly reduced l-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hcav1.2 by pkd.	SIGNOR-177481
P17252	P28329	1	phosphorylation	up-regulates	0.383	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129264
Q99661	O14965	0	phosphorylation	down-regulates activity	0.584	In addition, we found that MCAK localization at spindle poles was regulated through another Aurora A phosphorylation site (S719), which positively enhances bipolar spindle formation.	SIGNOR-279139
Q9Y4K3	P42345	1	ubiquitination	up-regulates activity	0.438	Together, these results demonstrate that mTOR polyubiquitination by TRAF6 modulates its activation in response to amino acids and point to a role for K63 ubiquitin modification as a sensor of nutrient status.	SIGNOR-278789
P28482	P49815	1	phosphorylation	down-regulates activity	0.681	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. \|Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-249454
Q9GZT5	O75197	2	binding	up-regulates	0.571	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-131619
P05023	P17252	0	phosphorylation	down-regulates activity	0.329	Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit.	SIGNOR-262941
P61586	Q9NR81	0	guanine nucleotide exchange factor	up-regulates activity	0.777	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-260530
P22681	P43405	1	ubiquitination	down-regulates quantity	0.816	Thus, c-Cbl specifically downregulates Syk levels in the presence of LMP2A.\|c-Cbl promoted LMP2A degradation through ubiquitination, specifically degraded the Syk protein tyrosine kinase in the presence of LMP2A, and inhibited LMP2A induction of the EBV lytic cycle	SIGNOR-278689
P55317	Q14938	2	binding	up-regulates	0.335	Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex.	SIGNOR-205082
Q05655	P16591	0	phosphorylation	up-regulates activity	0.2	We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface.	SIGNOR-277546
Q9P107	P63000	1	gtpase-activating protein	down-regulates activity	0.445	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-260506
P63092	Q14832	2	binding	up-regulates activity	0.35	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264083
P01189	P41968	2	binding	up-regulates activity	0.759	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268705
Q9Y297	P84022	1	ubiquitination	down-regulates	0.389	An e3 ubiquitin ligase complex roc1-scffbw1a consisting of roc1, skp1, cullin1, and fbw1a (also termed trcp1) induces ubiquitination of smad3.	SIGNOR-108237
Q13467	Q9ULT6	0	ubiquitination	down-regulates quantity	0.515	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260118
P36897	Q9UI12	2	binding	up-regulates activity	0.2	ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs.	SIGNOR-266886
Q04206	Q9H000	0	ubiquitination	down-regulates quantity by destabilization	0.341	MKRN2 promotes p65 ubiquitination and degradation through RING finger domain.	SIGNOR-278591
Q9NWZ3	P51617	1	phosphorylation	up-regulates activity	0.687	In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.	SIGNOR-117315
Q02156	P46940	1	phosphorylation	up-regulates	0.2	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-128718
O00141	O14686	1	phosphorylation	down-regulates activity	0.283	Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity.	SIGNOR-277447
Q969V5	O00429	1	sumoylation	up-regulates activity	0.534	Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.	SIGNOR-274128
P29353	P06241	0	phosphorylation	up-regulates	0.732	Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.	SIGNOR-59623
P43243	P35637	0	relocalization	up-regulates activity	0.486	Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates.	SIGNOR-262822
P25021	P09471	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257250
P55011	Q9H4A3	0	phosphorylation	up-regulates activity	0.491	Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS.	SIGNOR-277859
P06239	P32119	1	phosphorylation	down-regulates activity	0.2	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276279
P36956	Q14703	0	cleavage	up-regulates activity	0.561	We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2	SIGNOR-267497
Q9Y5Q3	P49841	0	phosphorylation	down-regulates	0.2	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159476
P10589	P19793	2	binding	up-regulates	0.549	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site	SIGNOR-79440
Q2T9J0	Q15067	1	cleavage	up-regulates activity	0.694	Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.	SIGNOR-261057
P13497	Q02388	1	cleavage	up-regulates quantity	0.604	We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen.	SIGNOR-256338
P25054	P17612	0	phosphorylation	down-regulates activity	0.307	Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization.	SIGNOR-250335
P48735	Q13309	0	ubiquitination	down-regulates quantity by destabilization	0.2	During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome	SIGNOR-267626
Q9Y5P4	Q15139	0	phosphorylation	down-regulates	0.2	In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity	SIGNOR-156500
P31751	Q7Z6J0	1	phosphorylation	down-regulates	0.389	Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac	SIGNOR-155233
P47712	O75582	0	phosphorylation	up-regulates activity	0.352	Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases.	SIGNOR-249051
P01241	P24385	1	transcriptional regulation	up-regulates quantity by expression	0.2	Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells	SIGNOR-261629
Q68DK2	Q6DKK2	2	binding	up-regulates activity	0.462	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. FYVE-CENT binds directly to TTC19 and KIF13A.	SIGNOR-265542
P29353	Q05397	0	phosphorylation	up-regulates activity	0.674	In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2.	SIGNOR-259854
P68400	Q02790	1	phosphorylation	down-regulates activity	0.343	Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. \| Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90	SIGNOR-250865
P14778	P53779	1	phosphorylation	up-regulates activity	0.2	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab	SIGNOR-249515
P35070	O14672	0	cleavage	up-regulates activity	0.372	Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin	SIGNOR-259839
Q92993	Q02156	0	phosphorylation	up-regulates activity	0.365	At least two TIP60 residues, Thr298 and Ser300, can be targeted in vitro by PKCepsilon.\|In vitro, protein kinase C epsilon phosphorylates Tat-interactive protein 60 kDa on at least two sites within the acetyltransferase domain.	SIGNOR-279309
P53350	Q96BK5	1	phosphorylation	down-regulates	0.361	Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation.	SIGNOR-166333
P50148	O43614	2	binding	up-regulates activity	0.45	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257216
Q86VW2	P60953	1	guanine nucleotide exchange factor	up-regulates	0.669	Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.	SIGNOR-235391
Q00987	Q09472	2	binding	down-regulates	0.687	Mdm2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins.	SIGNOR-84077
P40818	Q92783	2	binding	up-regulates quantity	0.535	Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells.	SIGNOR-266904
P53779	P05412	1	phosphorylation	up-regulates	0.887	With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation.	SIGNOR-164800
P27361	Q12929	1	phosphorylation	down-regulates activity	0.323	We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation.	SIGNOR-263058
Q68EM7	Q15642	2	binding	down-regulates activity	0.501	Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. \|ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex.	SIGNOR-272158
P08754	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-256874
P0C2W1	Q15672	2	binding	down-regulates quantity by destabilization	0.26	One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.	SIGNOR-272183
Q9BQ95	Q8IWR1	2	binding	down-regulates activity	0.518	In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.\|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.\|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities.	SIGNOR-260369
Q15717	Q16539	0	phosphorylation	up-regulates	0.523	P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna.	SIGNOR-186135
O95376	Q93034	2	binding	up-regulates activity	0.535	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268843
Q9ULX9	P35452	2	binding	down-regulates activity	0.381	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-221884
Q9UK99	Q9HCE7	2	binding	down-regulates quantity by destabilization	0.391	F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway.	SIGNOR-272441
P11362	Q9BV47	0	dephosphorylation	down-regulates activity	0.2	NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.\|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells	SIGNOR-277104
P62714	Q9NRL3	2	binding	up-regulates activity	0.588	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261699
Q15911	Q13315	0	phosphorylation	up-regulates activity	0.346	Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].\|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.	SIGNOR-279138
Q9NRW1	Q7Z7G8	2	binding	up-regulates activity	0.2	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization.	SIGNOR-266870
P55268	Q9NYD6	0	transcriptional regulation	up-regulates quantity by expression	0.2	The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.	SIGNOR-261645
Q8WUI4	Q9BZL6	0	phosphorylation	up-regulates activity	0.437	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275933
P05067	P56817	0	cleavage	up-regulates activity	0.794	Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ.	SIGNOR-255480
P35222	Q9P289	0	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
Q15078	Q9H0K1	0	phosphorylation	down-regulates	0.331	Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion	SIGNOR-204648
Q92888	O60674	0	phosphorylation	up-regulates	0.325	We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1	SIGNOR-163557
P16157	Q92823	0	relocalization	up-regulates quantity	0.544	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266721

P22681

O94875

1

ubiquitination

down-regulates

0.512

Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl

SIGNOR-96325

Q92600

Q6Y7W6

2

binding

up-regulates activity

0.2

Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2

SIGNOR-260058

Q13315

Q9BW19

1

phosphorylation

up-regulates quantity by stabilization

0.2

ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.

SIGNOR-277295

O00755

O75581

2

binding

up-regulates activity

0.648

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-131903

Q9UBN4

Q96J02

0

ubiquitination

down-regulates activity

0.35

Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.

SIGNOR-272624

Q15831

Q7KZI7

1

phosphorylation

up-regulates activity

0.588

MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase.

SIGNOR-276165

Q16875

O14920

0

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

Q92888

P17252

0

phosphorylation

up-regulates activity

0.439

We showed that the first and second phase of RhoA activity are dependent on p63 and Ca2+/PKC, respectively, and further identified phosphorylation of serine 240 on p115 RhoGEF by PKC to be the mechanistic link between PKC and RhoA.

SIGNOR-277530

P09471

Q9HBW0

2

binding

up-regulates activity

0.25

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

SIGNOR-257257

O75175

Q9Y6Q6

1

transcriptional regulation

down-regulates quantity by repression

0.2

Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis.

SIGNOR-261572

Q8TF76

P06493

0

phosphorylation

up-regulates activity

0.2

Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis.

SIGNOR-275419

Q16512

P10636

1

phosphorylation

down-regulates

0.329

Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly.

SIGNOR-84958

Q15038

Q9H2X6

0

phosphorylation

down-regulates activity

0.2

In response to DNA damage, HIPK2 phosphorylates DAZAP2 at several Ser/Thr residues including Ser77, which inhibits its HIPK2-degrading function and targets it to the cell nucleus.

SIGNOR-279335

Q9BXW4

Q14596

2

binding

down-regulates

0.53

We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.

SIGNOR-184258

P05771

Q9H1D0

1

phosphorylation

down-regulates activity

0.2

This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload.

SIGNOR-276265

P29274

P19086

2

binding

up-regulates activity

0.25

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

SIGNOR-257306

P13501

Q9BZS1

0

transcriptional regulation

up-regulates quantity by expression

0.434

Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression

SIGNOR-277727

Q9NQZ2

O00566

2

binding

up-regulates activity

0.934

Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome.

SIGNOR-261176

P24941

P30307

1

phosphorylation

up-regulates

0.754

The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.

SIGNOR-165872

P28482

Q86UC2

1

phosphorylation

up-regulates activity

0.2

ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). inhibiting ERK1/2 activity appears to negatively regulate the AKAP function of RSPH3.

SIGNOR-262839

Q14207

P24941

0

phosphorylation

up-regulates

0.447

Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.

SIGNOR-82141

Q99527

P50148

2

binding

up-regulates

0.2

However, grpr preferentially couples to galfaq proteins.

SIGNOR-195320

O15111

P06748

1

phosphorylation

up-regulates activity

0.2

S125A and a delta form lacking the aa 119-195 region completely abolished NPM phosphorylation by IKKalpha (XREF_FIG), suggesting that IKKalpha phosphorylates S125 of NPM.|We found that TNFalpha treatment induced IKKalpha phosphorylation and increased NPM hexamers, which were correlated with increased NPM phosphorylation (XREF_FIG).

SIGNOR-279405

Q8N392

Q6P5Z2

0

phosphorylation

up-regulates activity

0.2

We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158.

SIGNOR-264572

P17612

Q13972

1

phosphorylation

up-regulates

0.519

Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors.

SIGNOR-73202

P29474

P0DP24

2

binding

up-regulates activity

0.505

Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer

SIGNOR-266323

P00533

P27986

2

binding

up-regulates

0.81

The egf-r coimmunoprecipitated with p85 alpha

SIGNOR-121959

P14859

Q9UKX2

1

transcriptional regulation

up-regulates quantity by expression

0.2

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-238757

P16949

P27361

0

phosphorylation

down-regulates activity

0.577

Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs.

SIGNOR-249483

P17612

P16070

1

phosphorylation

up-regulates

0.2

Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains.

SIGNOR-147208

Q15139

Q13936

1

phosphorylation

up-regulates

0.255

Both the expression of a dominant-negative mutant of pkd and the mutation of serine 1884 but not serine 1930, putative targets of pkd, strongly reduced l-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hcav1.2 by pkd.

SIGNOR-177481

P17252

P28329

1

phosphorylation

up-regulates

0.383

We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.

SIGNOR-129264

Q99661

O14965

0

phosphorylation

down-regulates activity

0.584

In addition, we found that MCAK localization at spindle poles was regulated through another Aurora A phosphorylation site (S719), which positively enhances bipolar spindle formation.

SIGNOR-279139

Q9Y4K3

P42345

1

ubiquitination

up-regulates activity

0.438

Together, these results demonstrate that mTOR polyubiquitination by TRAF6 modulates its activation in response to amino acids and point to a role for K63 ubiquitin modification as a sensor of nutrient status.

SIGNOR-278789

P28482

P49815

1

phosphorylation

down-regulates activity

0.681

Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.

SIGNOR-249454

Q9GZT5

O75197

2

binding

up-regulates

0.571

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-131619

P05023

P17252

0

phosphorylation

down-regulates activity

0.329

Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit.

SIGNOR-262941

P61586

Q9NR81

0

guanine nucleotide exchange factor

up-regulates activity

0.777

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-260530

P22681

P43405

1

ubiquitination

down-regulates quantity

0.816

Thus, c-Cbl specifically downregulates Syk levels in the presence of LMP2A.|c-Cbl promoted LMP2A degradation through ubiquitination, specifically degraded the Syk protein tyrosine kinase in the presence of LMP2A, and inhibited LMP2A induction of the EBV lytic cycle

SIGNOR-278689

P55317

Q14938

2

binding

up-regulates

0.335

Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex.

SIGNOR-205082

Q05655

P16591

0

phosphorylation

up-regulates activity

0.2

We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface.

SIGNOR-277546

Q9P107

P63000

1

gtpase-activating protein

down-regulates activity

0.445

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-260506

P63092

Q14832

2

binding

up-regulates activity

0.35

MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.

SIGNOR-264083

P01189

P41968

2

binding

up-regulates activity

0.759

The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins

SIGNOR-268705

Q9Y297

P84022

1

ubiquitination

down-regulates

0.389

An e3 ubiquitin ligase complex roc1-scffbw1a consisting of roc1, skp1, cullin1, and fbw1a (also termed trcp1) induces ubiquitination of smad3.

SIGNOR-108237

Q13467

Q9ULT6

0

ubiquitination

down-regulates quantity

0.515

Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.

SIGNOR-260118

P36897

Q9UI12

2

binding

up-regulates activity

0.2

ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs.

SIGNOR-266886

Q04206

Q9H000

0

ubiquitination

down-regulates quantity by destabilization

0.341

MKRN2 promotes p65 ubiquitination and degradation through RING finger domain.

SIGNOR-278591

Q9NWZ3

P51617

1

phosphorylation

up-regulates activity

0.687

In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.

SIGNOR-117315

Q02156

P46940

1

phosphorylation

up-regulates

0.2

Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.

SIGNOR-128718

O00141

O14686

1

phosphorylation

down-regulates activity

0.283

Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity.

SIGNOR-277447

Q969V5

O00429

1

sumoylation

up-regulates activity

0.534

Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.

SIGNOR-274128

P29353

P06241

0

phosphorylation

up-regulates

0.732

Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.

SIGNOR-59623

P43243

P35637

0

relocalization

up-regulates activity

0.486

Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates.

SIGNOR-262822

P25021

P09471

2

binding

up-regulates activity

0.25

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

SIGNOR-257250

P55011

Q9H4A3

0

phosphorylation

up-regulates activity

0.491

Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS.

SIGNOR-277859

P06239

P32119

1

phosphorylation

down-regulates activity

0.2

Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.

SIGNOR-276279

P36956

Q14703

0

cleavage

up-regulates activity

0.561

We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2

SIGNOR-267497

Q9Y5Q3

P49841

0

phosphorylation

down-regulates

0.2

We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.

SIGNOR-159476

P10589

P19793

2

binding

up-regulates

0.549

Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site

SIGNOR-79440

Q2T9J0

Q15067

1

cleavage

up-regulates activity

0.694

Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.

SIGNOR-261057

P13497

Q02388

1

cleavage

up-regulates quantity

0.604

We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen.

SIGNOR-256338

P25054

P17612

0

phosphorylation

down-regulates activity

0.307

Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization.

SIGNOR-250335

P48735

Q13309

0

ubiquitination

down-regulates quantity by destabilization

0.2

During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome

SIGNOR-267626

Q9Y5P4

Q15139

0

phosphorylation

down-regulates

0.2

In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity

SIGNOR-156500

P31751

Q7Z6J0

1

phosphorylation

down-regulates

0.389

Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac

SIGNOR-155233

P47712

O75582

0

phosphorylation

up-regulates activity

0.352

Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases.

SIGNOR-249051

P01241

P24385

1

transcriptional regulation

up-regulates quantity by expression

0.2

Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells

SIGNOR-261629

Q68DK2

Q6DKK2

2

binding

up-regulates activity

0.462

We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. FYVE-CENT binds directly to TTC19 and KIF13A.

SIGNOR-265542

P29353

Q05397

0

phosphorylation

up-regulates activity

0.674

In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2.

SIGNOR-259854

P68400

Q02790

1

phosphorylation

down-regulates activity

0.343

Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90

SIGNOR-250865

P14778

P53779

1

phosphorylation

up-regulates activity

0.2

Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab

SIGNOR-249515

P35070

O14672

0

cleavage

up-regulates activity

0.372

Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin

SIGNOR-259839

Q92993

Q02156

0

phosphorylation

up-regulates activity

0.365

At least two TIP60 residues, Thr298 and Ser300, can be targeted in vitro by PKCepsilon.|In vitro, protein kinase C epsilon phosphorylates Tat-interactive protein 60 kDa on at least two sites within the acetyltransferase domain.

SIGNOR-279309

P53350

Q96BK5

1

phosphorylation

down-regulates

0.361

Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation.

SIGNOR-166333

P50148

O43614

2

binding

up-regulates activity

0.45

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

SIGNOR-257216

Q86VW2

P60953

1

guanine nucleotide exchange factor

up-regulates

0.669

Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.

SIGNOR-235391

Q00987

Q09472

2

binding

down-regulates

0.687

Mdm2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins.

SIGNOR-84077

P40818

Q92783

2

binding

up-regulates quantity

0.535

Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells.

SIGNOR-266904

P53779

P05412

1

phosphorylation

up-regulates

0.887

With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation.

SIGNOR-164800

P27361

Q12929

1

phosphorylation

down-regulates activity

0.323

We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation.

SIGNOR-263058

Q68EM7

Q15642

2

binding

down-regulates activity

0.501

Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex.

SIGNOR-272158

P08754

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-256874

P0C2W1

Q15672

2

binding

down-regulates quantity by destabilization

0.26

One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.

SIGNOR-272183

Q9BQ95

Q8IWR1

2

binding

down-regulates activity

0.518

In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities.

SIGNOR-260369

Q15717

Q16539

0

phosphorylation

up-regulates

0.523

P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna.

SIGNOR-186135

O95376

Q93034

2

binding

up-regulates activity

0.535

Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.

SIGNOR-268843

Q9ULX9

P35452

2

binding

down-regulates activity

0.381

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-221884

Q9UK99

Q9HCE7

2

binding

down-regulates quantity by destabilization

0.391

F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway.

SIGNOR-272441

P11362

Q9BV47

0

dephosphorylation

down-regulates activity

0.2

NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells

SIGNOR-277104

P62714

Q9NRL3

2

binding

up-regulates activity

0.588

The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms

SIGNOR-261699

Q15911

Q13315

0

phosphorylation

up-regulates activity

0.346

Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.

SIGNOR-279138

Q9NRW1

Q7Z7G8

2

binding

up-regulates activity

0.2

Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization.

SIGNOR-266870

P55268

Q9NYD6

0

transcriptional regulation

up-regulates quantity by expression

0.2

The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.

SIGNOR-261645

Q8WUI4

Q9BZL6

0

phosphorylation

up-regulates activity

0.437

Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].

SIGNOR-275933

P05067

P56817

0

cleavage

up-regulates activity

0.794

Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ.

SIGNOR-255480

P35222

Q9P289

0

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

Q15078

Q9H0K1

0

phosphorylation

down-regulates

0.331

Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion

SIGNOR-204648

Q92888

O60674

0

phosphorylation

up-regulates

0.325

We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1

SIGNOR-163557

P16157

Q92823

0

relocalization

up-regulates quantity

0.544

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266721