GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
Q9HAV7	P11142	1	binding	down-regulates activity	0.62	As we had observed earlier,HMGE bound avidly to DnaK (Fig. 5A). In addition, bothMt-Hsp70 and Hsc70 bound to GST-HMGE, but Hsc70 appeared to bind with lower affinity. HMGE inhibitedthe co-chaperone enhancement of Hsc70 ATPase activity byapproximately 50% (Table 1).	SIGNOR-261241
O43255	Q9Y6H5	1	ubiquitination	down-regulates	0.62	Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system	SIGNOR-140651
O15068	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.619	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-260559
P53350	Q8NHV4	1	phosphorylation	up-regulates activity	0.619	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272992
P68400	Q92769	1	phosphorylation	up-regulates	0.619	Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation.	SIGNOR-164795
Q6UW88	P00533	1	binding	up-regulates	0.619	Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.	SIGNOR-165779
P42574	P55212	1	cleavage	up-regulates	0.619	Caspase-3 is required for the activation of caspases 6	SIGNOR-64179
P06239	P43403	1	phosphorylation	up-regulates activity	0.619	We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck	SIGNOR-249375
Q13315	Q96SD1	1	phosphorylation	up-regulates	0.619	The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo	SIGNOR-148315
Q96RU7	P31749	1	binding	down-regulates activity	0.619	TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase.	SIGNOR-252644
Q96M96	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.619	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260554
Q96RR4	P54646	1	phosphorylation	up-regulates	0.619	These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo.	SIGNOR-138364
Q15759	Q8IW41	1	phosphorylation	up-regulates	0.619	Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site.	SIGNOR-58131
Q05209	P04626	1	dephosphorylation	down-regulates activity	0.619	In MDA-MB-231 cells, a human triple negative breast cancer cell line, phosphorylation of PTPN12 on Ser 19 was increased in response to cyclin dependent kinase 2 (CDK2), and this impaired PTPN12 's ability to dephosphorylate HER2 on Y1196.\|PTPN12 negatively regulates Her2, by dephosphorylation on Tyr 1196 on Her2.	SIGNOR-277038
Q16288	P19174	1	binding	up-regulates	0.619	Unglycosylated trka core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules shc and plc-gamma.	SIGNOR-67404
O60671	Q92547	1	binding	up-regulates	0.619	The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner	SIGNOR-179379
O00744	Q13467	1	binding	up-regulates	0.619	Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8	SIGNOR-210164
P04083	P25089	1	binding	up-regulates activity	0.618	We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.	SIGNOR-259438
Q14980	P23258	1	binding	up-regulates	0.618	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-117203
P22681	P10721	2	ubiquitination	down-regulates activity	0.618	KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT.	SIGNOR-260104
P08631	P40763	1	phosphorylation	up-regulates activity	0.618	Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. Direct Phosphorylation of STAT3 on Tyr-705 by Src Family Kinases	SIGNOR-251267
Q99683	O75460	1	phosphorylation	up-regulates activity	0.618	ASK1 may directly phosphorylate IRE1\u03b1 at sites other than the IRE1\u03b1 autophosphorylation site.	SIGNOR-279213
P10721	P22681	2	phosphorylation	up-regulates activity	0.618	The activated KIT in turn induces phosphorylation and activation of Cbl proteins.	SIGNOR-279199
P31749	P98170	1	phosphorylation	up-regulates quantity by stabilization	0.618	Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.	SIGNOR-119488
O14905	O75581	1	binding	up-regulates	0.618	We find that wnt9b binds to a different part of the lrp6 extracellular domain	SIGNOR-163552
P28482	O75582	1	phosphorylation	up-regulates	0.617	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-131311
Q6VAB6	P15056	1	binding	up-regulates activity	0.617	In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.	SIGNOR-273877
P24941	Q99708	1	phosphorylation	up-regulates	0.617	Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo	SIGNOR-183840
P23511	P08047	1	binding	up-regulates activity	0.617	Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response.	SIGNOR-254816
Q9NX18	P21912	1	binding	up-regulates	0.617	Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity	SIGNOR-187239
P00533	Q92529-2	1	phosphorylation	up-regulates activity	0.617	We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.	SIGNOR-273922
P10586	Q9NT99	1	binding	up-regulates activity	0.617	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264049
O60674	Q92783	1	phosphorylation	up-regulates	0.617	Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2.	SIGNOR-47834
Q9UBV4	Q9NPG1	1	binding	up-regulates	0.617	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-131674
Q93098	O75581	1	binding	up-regulates	0.617	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-132027
O60674	P04049	1	phosphorylation	up-regulates activity	0.617	JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.	SIGNOR-251361
O00744	Q9NPG1	1	binding	up-regulates	0.617	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131625
P27361	Q9UQC2	1	phosphorylation	up-regulates	0.617	Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.	SIGNOR-128731
P42574	Q13043	1	cleavage	up-regulates activity	0.617	In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus.	SIGNOR-109878
Q12774	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.617	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260533
P00533	Q92529	1	binding	up-regulates	0.617	Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc).	SIGNOR-55861
Q13464	P53667	1	phosphorylation	up-regulates activity	0.617	Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop.	SIGNOR-74569
P37231	Q13547	1	relocalization	down-regulates	0.617	These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome	SIGNOR-143961
Q13217	Q9NZJ5	1	binding	down-regulates activity	0.616	The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK	SIGNOR-246201
P29317	P29353	1	binding	up-regulates	0.616	We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases.	SIGNOR-94804
P17600	P20336	1	binding	up-regulates activity	0.616	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. The interaction between synapsin I and Rab3A was confirmed by photoaffinity labeling experiments on purified synaptic vesicles and by the formation of a chemically cross-linked complex between synapsin I and Rab3A in intact nerve terminals. The data indicate that synapsin I is a novel Rab3 interactor on synaptic vesicles and suggest that the synapsin-Rab3 interaction may participate in the regulation of synaptic vesicle trafficking within the nerve terminals.	SIGNOR-269181
P78362	Q07955	1	phosphorylation	up-regulates activity	0.616	In contrast, SRPK1 or SRPK2 overexpression upregulated the phosphorylation and nucleus accumulation of SRSF1.\|Therefore, SRPK1 and SRPK2 may directly phosphorylate SRSF1 and promote it nucleus translocation, subsequently modulate MKNK2 alternative splicing.	SIGNOR-279660
Q92793	P15172	1	acetylation	up-regulates	0.616	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81050
Q15759	O75582	1	phosphorylation	up-regulates	0.615	Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha	SIGNOR-59443
P12931	P04626	1	phosphorylation	up-regulates activity	0.615	In addition, the c-Src inhibitor 4-(4\u2019-phenoxyanilino)-6,7-dimethoxyquinazoline prevented SP-induced activation of HER2.\|On the other hand, c-Src directly phosphorylates the cytoplasmic tails of both EGFR and HER2, allowing the binding of scaffold proteins that will further activate signal transduction.	SIGNOR-279432
Q6EBC2	Q99650	1	binding	up-regulates	0.615	Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor.	SIGNOR-125347
Q00534	Q01196	1	phosphorylation	up-regulates	0.615	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138953
P40763	P42224	1	transcriptional regulation	up-regulates quantity by expression	0.615	In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression.	SIGNOR-263650
O75676	P18846	1	phosphorylation	up-regulates	0.615	Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1.	SIGNOR-116252
P38435	P00742	1	carboxylation	up-regulates activity	0.615	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. \|We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.\|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; \| 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263667
P09619	O43639	1	binding	up-regulates	0.615	The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency.	SIGNOR-64740
P38405	O95622	1	binding	up-regulates activity	0.615	D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.	SIGNOR-264997
Q9UHA4	Q02750	1	binding	up-regulates	0.615	We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations.	SIGNOR-130924
Q13535	Q99708	1	phosphorylation	up-regulates	0.615	Characterization of this site using phospho-specific antibodies and mutational analysis reveals that it is phosphorylated by atr and is required for binding of ctip to chromatin and subsequent processive resection.	SIGNOR-200245
Q13671	P42684	2	phosphorylation	up-regulates	0.615	Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl	SIGNOR-136961
P42684	Q13671	2	phosphorylation	up-regulates activity	0.615	These findings suggested that RIN1 is phosphorylated by both ABL1 and ABL2.	SIGNOR-279676
Q13418	P31751	1	phosphorylation	up-regulates activity	0.615	ILK mediated activation of Akt2 is required for Tbeta4 inducible expression of MMP-2 and EC motility.\|Our experiments suggest that ILK phosphorylates Akt2 at Ser474, that Akt2 is a better substrate than Akt1, and that a post-translational modification to ILK is required for its activity.	SIGNOR-279055
Q15366	Q96J02	1	binding	up-regulates activity	0.615	Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS	SIGNOR-260361
P16333	Q07889	1	binding	up-regulates	0.615	We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located.	SIGNOR-236321
P12931	P20936	1	phosphorylation	down-regulates	0.615	The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity	SIGNOR-86008
P12931	P63000	1	phosphorylation	up-regulates activity	0.615	In addition, Rac1 is phosphorylated at Y64 by FAK and Src kinases ( xref ); Y64 phosphorylation targets Rac1 to focal adhesions.	SIGNOR-280132
P26951	O60674	1	binding	up-regulates	0.615	Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a.	SIGNOR-134859
Q9HCE7	P37173	1	ubiquitination	down-regulates activity	0.615	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195672
Q8IU54	Q08334	1	binding	up-regulates	0.615	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96177
P49757	Q96J02	1	binding	up-regulates	0.615	Numb activates the catalytic activity of itch, releasing it from an inhibitory intramolecular interaction between its homologous to e6-ap c-terminus and ww domains.	SIGNOR-167844
P01562	P48551	1	binding	up-regulates activity	0.614	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-219298
P16298	Q13469	1	dephosphorylation	up-regulates	0.614	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-233438
P35368	P50148	1	binding	up-regulates activity	0.614	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-257079
Q96J02	O15519	1	ubiquitination	down-regulates quantity	0.614	Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.	SIGNOR-245307
P22681	P00519	1	ubiquitination	down-regulates quantity by destabilization	0.614	We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins	SIGNOR-167194
Q9UHD2	Q04206	1	phosphorylation	up-regulates	0.614	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129951
Q13153	P53667	1	phosphorylation	up-regulates activity	0.614	Activation of lim-kinase by pak1 couplesp21-activated kinase (pak1) phosphorylates lim-kinase at threonine residue 508 within lim-kinase's activation loop	SIGNOR-72142
P12931	P35968	1	phosphorylation	up-regulates activity	0.614	In contrast, our analysis showed that over-expression of c-Src significantly enhances the ability of VEGFR-2 to stimulate proliferation of PAE cells and over-expression of dominant negative Src (Src kinase-dead) inhibits the VEGFR-2 driven proliferation of PAE cells (XREF_FIG).\|Taken together, the data demonstrate that Src kinases upon activation by VEGFR-2 phosphorylate Y1173 of VEGFR-2 (XREF_FIG).	SIGNOR-279120
P49674	P25054	1	phosphorylation	up-regulates activity	0.614	Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin.	SIGNOR-109664
P23443	Q53EL6	1	phosphorylation	down-regulates	0.614	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-150144
Q9ULT6	O60353	1	ubiquitination	down-regulates quantity	0.614	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-260114
P06241	O75553	1	phosphorylation	down-regulates activity	0.614	Tyrosine phosphorylation of Dab1 by Fyn inhibits its interaction with APP, while increasing its interaction with Fyn.	SIGNOR-278476
Q9NTX7	Q9H2K2	1	ubiquitination	down-regulates quantity	0.614	We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260005
O75385	Q9Y4P1	1	phosphorylation	down-regulates activity	0.614	Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316.\|Thus ULK1 is able to inhibit LC3 processing by a direct effect on ATG4B, possibly by phosphorylation of a serine residue of ATG4B.Fig. 1ULK1 inhibits ATG4B-mediated LC3 cleavage. a Average ATG4B activity in Actin-LC3-DelN Luciferase HEK293T obtained by measuring the secreted luciferase activity 48 h after transfection with the indicated constructs (n = 3, average \u00b1 s.d.) and representative immunoblot from one experiment showing expression of the different constructs. b GST-LC3 assay to measure in vitro activity of recombinant ATG4B after incubation with active recombinant ULK1.	SIGNOR-279434
P07949	Q99704	1	binding	up-regulates	0.614	Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret.	SIGNOR-90158
P10721	O60674	1	binding	up-regulates activity	0.614	C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit	SIGNOR-254954
Q9UBE8	Q12778	1	phosphorylation	down-regulates activity	0.613	Here, we report that the transforming growth factor-beta-activated kinase (TAK1)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1. We show that NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain. The phosphorylation by TAK1-NLK pathway inhibits the transcriptional activity of FOXO1 and excludes FOXO1 from the nucleus, which is independent of phosphatidylinositol 3-kinase/Akt pathway.	SIGNOR-273907
Q9H300	Q9BXM7	1	cleavage	down-regulates quantity by destabilization	0.613	Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy.	SIGNOR-261364
P20382	Q969V1	1	binding	up-regulates	0.613	Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor.	SIGNOR-70520
P31749	P05106	1	phosphorylation	down-regulates activity	0.613	A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules.	SIGNOR-252552
P55347	P14653	1	binding	up-regulates activity	0.613	we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target.	SIGNOR-241215
Q969H0	P46531	1	ubiquitination	down-regulates quantity by destabilization	0.613	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-130706
P06239	P29350	2	phosphorylation	up-regulates activity	0.613	Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. .	SIGNOR-251387
O15105	P84022	1	transcriptional regulation	down-regulates quantity	0.613	The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression	SIGNOR-260437
Q99683	P52564	1	phosphorylation	up-regulates activity	0.613	A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively.	SIGNOR-45353
P04626	P00533	2	binding	up-regulates	0.613	Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3.	SIGNOR-147838
P38435	P07225	1	carboxylation	up-regulates activity	0.613	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265924
P00533	P04626	2	phosphorylation	up-regulates activity	0.613	Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. \| In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation.	SIGNOR-251094
P29350	P06239	2	dephosphorylation	down-regulates activity	0.613	We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck.	SIGNOR-106604
P45983	P98177	1	phosphorylation	up-regulates	0.612	Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment.	SIGNOR-130385

Q9HAV7

P11142

1

binding

down-regulates activity

0.62

As we had observed earlier,HMGE bound avidly to DnaK (Fig. 5A). In addition, bothMt-Hsp70 and Hsc70 bound to GST-HMGE, but Hsc70 appeared to bind with lower affinity. HMGE inhibitedthe co-chaperone enhancement of Hsc70 ATPase activity byapproximately 50% (Table 1).

SIGNOR-261241

O43255

Q9Y6H5

1

ubiquitination

down-regulates

0.62

Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system

SIGNOR-140651

O15068

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.619

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-260559

P53350

Q8NHV4

1

phosphorylation

up-regulates activity

0.619

Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.

SIGNOR-272992

P68400

Q92769

1

phosphorylation

up-regulates

0.619

Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation.

SIGNOR-164795

Q6UW88

P00533

1

binding

up-regulates

0.619

Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.

SIGNOR-165779

P42574

P55212

1

cleavage

up-regulates

0.619

Caspase-3 is required for the activation of caspases 6

SIGNOR-64179

P06239

P43403

1

phosphorylation

up-regulates activity

0.619

We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck

SIGNOR-249375

Q13315

Q96SD1

1

phosphorylation

up-regulates

0.619

The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo

SIGNOR-148315

Q96RU7

P31749

1

binding

down-regulates activity

0.619

TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase.

SIGNOR-252644

Q96M96

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.619

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

SIGNOR-260554

Q96RR4

P54646

1

phosphorylation

up-regulates

0.619

These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo.

SIGNOR-138364

Q15759

Q8IW41

1

phosphorylation

up-regulates

0.619

Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site.

SIGNOR-58131

Q05209

P04626

1

dephosphorylation

down-regulates activity

0.619

In MDA-MB-231 cells, a human triple negative breast cancer cell line, phosphorylation of PTPN12 on Ser 19 was increased in response to cyclin dependent kinase 2 (CDK2), and this impaired PTPN12 's ability to dephosphorylate HER2 on Y1196.|PTPN12 negatively regulates Her2, by dephosphorylation on Tyr 1196 on Her2.

SIGNOR-277038

Q16288

P19174

1

binding

up-regulates

0.619

Unglycosylated trka core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules shc and plc-gamma.

SIGNOR-67404

O60671

Q92547

1

binding

up-regulates

0.619

The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner

SIGNOR-179379

O00744

Q13467

1

binding

up-regulates

0.619

Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8

SIGNOR-210164

P04083

P25089

1

binding

up-regulates activity

0.618

We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.

SIGNOR-259438

Q14980

P23258

1

binding

up-regulates

0.618

Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.

SIGNOR-117203

P22681

P10721

2

ubiquitination

down-regulates activity

0.618

KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT.

SIGNOR-260104

P08631

P40763

1

phosphorylation

up-regulates activity

0.618

Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. Direct Phosphorylation of STAT3 on Tyr-705 by Src Family Kinases

SIGNOR-251267

Q99683

O75460

1

phosphorylation

up-regulates activity

0.618

ASK1 may directly phosphorylate IRE1\u03b1 at sites other than the IRE1\u03b1 autophosphorylation site.

SIGNOR-279213

P10721

P22681

2

phosphorylation

up-regulates activity

0.618

The activated KIT in turn induces phosphorylation and activation of Cbl proteins.

SIGNOR-279199

P31749

P98170

1

phosphorylation

up-regulates quantity by stabilization

0.618

Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.

SIGNOR-119488

O14905

O75581

1

binding

up-regulates

0.618

We find that wnt9b binds to a different part of the lrp6 extracellular domain

SIGNOR-163552

P28482

O75582

1

phosphorylation

up-regulates

0.617

Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.

SIGNOR-131311

Q6VAB6

P15056

1

binding

up-regulates activity

0.617

In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.

SIGNOR-273877

P24941

Q99708

1

phosphorylation

up-regulates

0.617

Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo

SIGNOR-183840

P23511

P08047

1

binding

up-regulates activity

0.617

Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response.

SIGNOR-254816

Q9NX18

P21912

1

binding

up-regulates

0.617

Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity

SIGNOR-187239

P00533

Q92529-2

1

phosphorylation

up-regulates activity

0.617

We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.

SIGNOR-273922

P10586

Q9NT99

1

binding

up-regulates activity

0.617

The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.

SIGNOR-264049

O60674

Q92783

1

phosphorylation

up-regulates

0.617

Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2.

SIGNOR-47834

Q9UBV4

Q9NPG1

1

binding

up-regulates

0.617

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-131674

Q93098

O75581

1

binding

up-regulates

0.617

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-132027

O60674

P04049

1

phosphorylation

up-regulates activity

0.617

JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.

SIGNOR-251361

O00744

Q9NPG1

1

binding

up-regulates

0.617

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

SIGNOR-131625

P27361

Q9UQC2

1

phosphorylation

up-regulates

0.617

Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.

SIGNOR-128731

P42574

Q13043

1

cleavage

up-regulates activity

0.617

In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus.

SIGNOR-109878

Q12774

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.617

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

SIGNOR-260533

P00533

Q92529

1

binding

up-regulates

0.617

Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc).

SIGNOR-55861

Q13464

P53667

1

phosphorylation

up-regulates activity

0.617

Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop.

SIGNOR-74569

P37231

Q13547

1

relocalization

down-regulates

0.617

These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome

SIGNOR-143961

Q13217

Q9NZJ5

1

binding

down-regulates activity

0.616

The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK

SIGNOR-246201

P29317

P29353

1

binding

up-regulates

0.616

We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases.

SIGNOR-94804

P17600

P20336

1

binding

up-regulates activity

0.616

Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. The interaction between synapsin I and Rab3A was confirmed by photoaffinity labeling experiments on purified synaptic vesicles and by the formation of a chemically cross-linked complex between synapsin I and Rab3A in intact nerve terminals. The data indicate that synapsin I is a novel Rab3 interactor on synaptic vesicles and suggest that the synapsin-Rab3 interaction may participate in the regulation of synaptic vesicle trafficking within the nerve terminals.

SIGNOR-269181

P78362

Q07955

1

phosphorylation

up-regulates activity

0.616

In contrast, SRPK1 or SRPK2 overexpression upregulated the phosphorylation and nucleus accumulation of SRSF1.|Therefore, SRPK1 and SRPK2 may directly phosphorylate SRSF1 and promote it nucleus translocation, subsequently modulate MKNK2 alternative splicing.

SIGNOR-279660

Q92793

P15172

1

acetylation

up-regulates

0.616

Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.

SIGNOR-81050

Q15759

O75582

1

phosphorylation

up-regulates

0.615

Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha

SIGNOR-59443

P12931

P04626

1

phosphorylation

up-regulates activity

0.615

In addition, the c-Src inhibitor 4-(4\u2019-phenoxyanilino)-6,7-dimethoxyquinazoline prevented SP-induced activation of HER2.|On the other hand, c-Src directly phosphorylates the cytoplasmic tails of both EGFR and HER2, allowing the binding of scaffold proteins that will further activate signal transduction.

SIGNOR-279432

Q6EBC2

Q99650

1

binding

up-regulates

0.615

Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor.

SIGNOR-125347

Q00534

Q01196

1

phosphorylation

up-regulates

0.615

We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.

SIGNOR-138953

P40763

P42224

1

transcriptional regulation

up-regulates quantity by expression

0.615

In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression.

SIGNOR-263650

O75676

P18846

1

phosphorylation

up-regulates

0.615

Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1.

SIGNOR-116252

P38435

P00742

1

carboxylation

up-regulates activity

0.615

This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).

SIGNOR-263667

P09619

O43639

1

binding

up-regulates

0.615

The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency.

SIGNOR-64740

P38405

O95622

1

binding

up-regulates activity

0.615

D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.

SIGNOR-264997

Q9UHA4

Q02750

1

binding

up-regulates

0.615

We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations.

SIGNOR-130924

Q13535

Q99708

1

phosphorylation

up-regulates

0.615

Characterization of this site using phospho-specific antibodies and mutational analysis reveals that it is phosphorylated by atr and is required for binding of ctip to chromatin and subsequent processive resection.

SIGNOR-200245

Q13671

P42684

2

phosphorylation

up-regulates

0.615

Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl

SIGNOR-136961

P42684

Q13671

2

phosphorylation

up-regulates activity

0.615

These findings suggested that RIN1 is phosphorylated by both ABL1 and ABL2.

SIGNOR-279676

Q13418

P31751

1

phosphorylation

up-regulates activity

0.615

ILK mediated activation of Akt2 is required for Tbeta4 inducible expression of MMP-2 and EC motility.|Our experiments suggest that ILK phosphorylates Akt2 at Ser474, that Akt2 is a better substrate than Akt1, and that a post-translational modification to ILK is required for its activity.

SIGNOR-279055

Q15366

Q96J02

1

binding

up-regulates activity

0.615

Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS

SIGNOR-260361

P16333

Q07889

1

binding

up-regulates

0.615

We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located.

SIGNOR-236321

P12931

P20936

1

phosphorylation

down-regulates

0.615

The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity

SIGNOR-86008

P12931

P63000

1

phosphorylation

up-regulates activity

0.615

In addition, Rac1 is phosphorylated at Y64 by FAK and Src kinases ( xref ); Y64 phosphorylation targets Rac1 to focal adhesions.

SIGNOR-280132

P26951

O60674

1

binding

up-regulates

0.615

Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a.

SIGNOR-134859

Q9HCE7

P37173

1

ubiquitination

down-regulates activity

0.615

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.

SIGNOR-195672

Q8IU54

Q08334

1

binding

up-regulates

0.615

Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.

SIGNOR-96177

P49757

Q96J02

1

binding

up-regulates

0.615

Numb activates the catalytic activity of itch, releasing it from an inhibitory intramolecular interaction between its homologous to e6-ap c-terminus and ww domains.

SIGNOR-167844

P01562

P48551

1

binding

up-regulates activity

0.614

Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.

SIGNOR-219298

P16298

Q13469

1

dephosphorylation

up-regulates

0.614

Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.

SIGNOR-233438

P35368

P50148

1

binding

up-regulates activity

0.614

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-257079

Q96J02

O15519

1

ubiquitination

down-regulates quantity

0.614

Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.

SIGNOR-245307

P22681

P00519

1

ubiquitination

down-regulates quantity by destabilization

0.614

We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins

SIGNOR-167194

Q9UHD2

Q04206

1

phosphorylation

up-regulates

0.614

Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.

SIGNOR-129951

Q13153

P53667

1

phosphorylation

up-regulates activity

0.614

Activation of lim-kinase by pak1 couplesp21-activated kinase (pak1) phosphorylates lim-kinase at threonine residue 508 within lim-kinase's activation loop

SIGNOR-72142

P12931

P35968

1

phosphorylation

up-regulates activity

0.614

In contrast, our analysis showed that over-expression of c-Src significantly enhances the ability of VEGFR-2 to stimulate proliferation of PAE cells and over-expression of dominant negative Src (Src kinase-dead) inhibits the VEGFR-2 driven proliferation of PAE cells (XREF_FIG).|Taken together, the data demonstrate that Src kinases upon activation by VEGFR-2 phosphorylate Y1173 of VEGFR-2 (XREF_FIG).

SIGNOR-279120

P49674

P25054

1

phosphorylation

up-regulates activity

0.614

Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin.

SIGNOR-109664

P23443

Q53EL6

1

phosphorylation

down-regulates

0.614

Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.

SIGNOR-150144

Q9ULT6

O60353

1

ubiquitination

down-regulates quantity

0.614

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-260114

P06241

O75553

1

phosphorylation

down-regulates activity

0.614

Tyrosine phosphorylation of Dab1 by Fyn inhibits its interaction with APP, while increasing its interaction with Fyn.

SIGNOR-278476

Q9NTX7

Q9H2K2

1

ubiquitination

down-regulates quantity

0.614

We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.

SIGNOR-260005

O75385

Q9Y4P1

1

phosphorylation

down-regulates activity

0.614

Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316.|Thus ULK1 is able to inhibit LC3 processing by a direct effect on ATG4B, possibly by phosphorylation of a serine residue of ATG4B.Fig. 1ULK1 inhibits ATG4B-mediated LC3 cleavage. a Average ATG4B activity in Actin-LC3-DelN Luciferase HEK293T obtained by measuring the secreted luciferase activity 48 h after transfection with the indicated constructs (n = 3, average \u00b1 s.d.) and representative immunoblot from one experiment showing expression of the different constructs. b GST-LC3 assay to measure in vitro activity of recombinant ATG4B after incubation with active recombinant ULK1.

SIGNOR-279434

P07949

Q99704

1

binding

up-regulates

0.614

Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret.

SIGNOR-90158

P10721

O60674

1

binding

up-regulates activity

0.614

C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit

SIGNOR-254954

Q9UBE8

Q12778

1

phosphorylation

down-regulates activity

0.613

Here, we report that the transforming growth factor-beta-activated kinase (TAK1)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1. We show that NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain. The phosphorylation by TAK1-NLK pathway inhibits the transcriptional activity of FOXO1 and excludes FOXO1 from the nucleus, which is independent of phosphatidylinositol 3-kinase/Akt pathway.

SIGNOR-273907

Q9H300

Q9BXM7

1

cleavage

down-regulates quantity by destabilization

0.613

Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy.

SIGNOR-261364

P20382

Q969V1

1

binding

up-regulates

0.613

Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor.

SIGNOR-70520

P31749

P05106

1

phosphorylation

down-regulates activity

0.613

A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules.

SIGNOR-252552

P55347

P14653

1

binding

up-regulates activity

0.613

we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target.

SIGNOR-241215

Q969H0

P46531

1

ubiquitination

down-regulates quantity by destabilization

0.613

Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.

SIGNOR-130706

P06239

P29350

2

phosphorylation

up-regulates activity

0.613

Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. .

SIGNOR-251387

O15105

P84022

1

transcriptional regulation

down-regulates quantity

0.613

The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression

SIGNOR-260437

Q99683

P52564

1

phosphorylation

up-regulates activity

0.613

A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively.

SIGNOR-45353

P04626

P00533

2

binding

up-regulates

0.613

Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3.

SIGNOR-147838

P38435

P07225

1

carboxylation

up-regulates activity

0.613

Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z

SIGNOR-265924

P00533

P04626

2

phosphorylation

up-regulates activity

0.613

Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. | In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation.

SIGNOR-251094

P29350

P06239

2

dephosphorylation

down-regulates activity

0.613

We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck.

SIGNOR-106604

P45983

P98177

1

phosphorylation

up-regulates

0.612

Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment.

SIGNOR-130385