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
P28702	P55055	1	binding	up-regulates	0.696	We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.	SIGNOR-123094
O60674	P46527	1	phosphorylation	down-regulates activity	0.696	JAK2 phosphorylates tyrosine residue 88 (Y88) of p27(Kip1).	SIGNOR-278260
P12931	P60953	1	phosphorylation	up-regulates	0.695	Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation.	SIGNOR-118206
Q9Y6W6	Q16539	1	dephosphorylation	down-regulates	0.695	Mkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk, but not mapk/erk. p38 is a preferred substrate	SIGNOR-68983
P55072	Q96IV0	1	binding	up-regulates activity	0.695	PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.	SIGNOR-261058
P42684	P46108	1	phosphorylation	down-regulates	0.695	Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations.	SIGNOR-136958
P08581	P62993	1	binding	up-regulates activity	0.695	For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS.	SIGNOR-256261
Q96EB6	P37231	1	transcriptional regulation	down-regulates quantity by repression	0.695	Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms.	SIGNOR-268032
P51955	Q5T7B8	1	phosphorylation	up-regulates activity	0.695	Nek2 binds and phosphorylates Kif24.\|We also provide evidence that Nek2 dependent phosphorylation induces a conformational change in Kif24 that promotes its activity.	SIGNOR-278413
Q6P1J9	P35222	1	binding	up-regulates	0.695	Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo	SIGNOR-146282
P33981	O43683	1	phosphorylation	up-regulates activity	0.695	After Cdk1 phosphorylates Bub1 S459, Mps1 then phosphorylates Bub1 T461 (b).	SIGNOR-278255
P08253	P07585	1	cleavage	down-regulates quantity by destabilization	0.695	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256350
P27361	Q16665	1	phosphorylation	up-regulates	0.695	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-178731
Q8NFG4	Q9HB90	1	gtpase-activating protein	up-regulates activity	0.695	The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur	SIGNOR-256503
O75474	P49841	1	binding	down-regulates activity	0.695	The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation.	SIGNOR-244030
O75385	Q9C0C7	1	phosphorylation	up-regulates	0.695	When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation.	SIGNOR-168292
P12931	P46940	1	phosphorylation	up-regulates activity	0.695	IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET.	SIGNOR-277533
Q14232	P41091	1	guanine nucleotide exchange factor	up-regulates activity	0.694	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269134
Q99836	Q13114	1	binding	up-regulates activity	0.694	Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6.	SIGNOR-256079
Q9HCE7	P36897	1	polyubiquitination	down-regulates quantity by destabilization	0.694	Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.	SIGNOR-272943
Q15628	Q13077	1	binding	up-regulates	0.694	Tradd mediates recruitment of traf1/2	SIGNOR-73913
P19793	P55055	1	binding	up-regulates	0.694	We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.	SIGNOR-123091
P25445	Q99683	1	binding	up-regulates	0.694	Ask1 binds fas	SIGNOR-109676
P27361	P49815	1	phosphorylation	down-regulates activity	0.694	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-249457
O94856	Q01484	1	relocalization	up-regulates quantity	0.694	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-266716
P22681	P27986	1	ubiquitination	down-regulates	0.694	Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.	SIGNOR-110060
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
P56211	Q66LE6	1	binding	down-regulates activity	0.694	We identified cyclic adenosine monophosphateregulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.	SIGNOR-243731
P54646	Q8N122	1	phosphorylation	down-regulates activity	0.693	These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.\|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK	SIGNOR-163463
P35240	Q9NRM7	1	binding	up-regulates	0.693	As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2	SIGNOR-202607
P67775	Q13188	1	dephosphorylation	down-regulates	0.693	Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.	SIGNOR-201266
P34130	P04629	1	binding	up-regulates	0.693	Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.	SIGNOR-85117
P49674	O14641	1	phosphorylation	up-regulates	0.693	We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197555
Q9NQS7	O14965	2	binding	up-regulates activity	0.693	INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop	SIGNOR-252048
O14965	Q9NQS7	2	phosphorylation	up-regulates activity	0.693	INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop	SIGNOR-252047
Q86YT6	P78504	1	ubiquitination	up-regulates activity	0.693	Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum.	SIGNOR-97388
O60674	O14744	1	phosphorylation	down-regulates	0.693	Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity	SIGNOR-171994
P27361	P35236	1	phosphorylation	up-regulates activity	0.693	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.\|	SIGNOR-249475
Q6UXX9	O75473	1	binding	up-regulates	0.693	Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation	SIGNOR-174532
P28482	P30041	1	phosphorylation	up-regulates	0.693	These results show that the mapks can mediate phosphorylation of prdx6 at thr-177 with a consequent marked increase in its aipla(2) activity.	SIGNOR-183379
Q9Y3M2	P35222	1	binding	down-regulates	0.693	Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin.	SIGNOR-100835
Q12770	P36956	1	binding	up-regulates activity	0.692	Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis.	SIGNOR-256210
P56524	Q14814	1	binding	down-regulates	0.692	We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.	SIGNOR-76237
O14920	O43524	1	phosphorylation	down-regulates	0.692	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-124207
P17252	O14939	1	phosphorylation	up-regulates	0.692	The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity	SIGNOR-138355
P62834	P15056	1	binding	up-regulates activity	0.692	Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis).	SIGNOR-276608
O75962	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.692	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-260579
P06239	P07766	1	phosphorylation	up-regulates activity	0.692	Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways.	SIGNOR-251369
P01303	P50391	1	binding	up-regulates	0.692	Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.	SIGNOR-29633
P04628	O60353	1	binding	up-regulates activity	0.692	Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway.	SIGNOR-198846
Q04206	P05231	1	transcriptional regulation	up-regulates quantity by expression	0.692	Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation	SIGNOR-251737
P15498	P22681	1	binding	up-regulates	0.692	Hese data imply that c-cbl is a molecular adapter that regulates the function of vav	SIGNOR-49188
P30304	P20248	1	dephosphorylation	up-regulates activity	0.692	Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1 [4,5] .	SIGNOR-277136
Q96SN8	Q96MT8	1	relocalization	up-regulates activity	0.692	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271722
Q9NRF2	O60674	1	binding	up-regulates activity	0.692	The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex	SIGNOR-253078
Q8IU81	P14316	1	binding	up-regulates activity	0.692	We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.	SIGNOR-224045
P18031	P09619	1	dephosphorylation	down-regulates	0.691	Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.	SIGNOR-179064
Q13705	P36896	1	phosphorylation	up-regulates activity	0.691	Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.	SIGNOR-235146
P04637	Q16611	1	binding	up-regulates	0.691	P53 interacts with the pro-apoptotic mitochondrial membrane protein bak	SIGNOR-124122
P98170	P60484	1	ubiquitination	down-regulates quantity	0.691	Finally, we found that XIAP can directly ubiquitinate PTEN in vitro.\|Overexpression of XIAP induces polyubiquitination of PTEN and proteasome dependent decrease of PTEN protein levels.	SIGNOR-278751
P49137	P16220	1	phosphorylation	up-regulates activity	0.691	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2.	SIGNOR-166619
P49841	P16220	1	phosphorylation	up-regulates activity	0.691	GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant	SIGNOR-251233
P46020	Q16816	1	binding	down-regulates activity	0.691	Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267405
Q9H4P4	P21860	1	polyubiquitination	down-regulates quantity by destabilization	0.691	Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3	SIGNOR-272599
Q9UQ13	O14807	1	binding	up-regulates	0.69	Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf.	SIGNOR-77082
Q08881	P10747	1	phosphorylation	up-regulates	0.69	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-198747
O75582	P18846	1	phosphorylation	up-regulates activity	0.69	Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. \| Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts	SIGNOR-249144
Q8TD19	Q9HC98	1	phosphorylation	up-regulates activity	0.69	Nercc1/nek9 activates the nek6 and nek7 kinases. Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant nek6 at ser206 in vitro concomitant with 20-25-fold activation of nek6 activity.	SIGNOR-102996
Q13705	P84022	1	phosphorylation	up-regulates activity	0.69	It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains	SIGNOR-254985
Q8WWW0	P01116	1	binding	up-regulates activity	0.69	NORE1A can bind K-Ras.GTP through its RA domain and regulate the proapoptotic activity of MST1/2 kinases	SIGNOR-249586
Q13418	P49841	1	phosphorylation	down-regulates activity	0.69	ILK can also directly phosphorylates GSK-3\u03b2 at Ser 9, inactivate it, and lead to activation of some transcription factors [ ].\|ILK knockdown activates GSK-3beta.	SIGNOR-278252
P35222	P15884	1	binding	up-regulates activity	0.69	beta-catenin interacts with the TCF/Lef family transcription factors.	SIGNOR-178042
Q05397	O00401	1	phosphorylation	up-regulates activity	0.69	In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.	SIGNOR-278977
Q16659	Q8IW41	1	phosphorylation	up-regulates activity	0.69	ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5.	SIGNOR-279073
O14641	O75581	1	binding	up-regulates activity	0.69	Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction.	SIGNOR-66362
Q92793	Q06413	1	binding	up-regulates	0.689	The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.	SIGNOR-83843
P35240	O95835	1	binding	up-regulates	0.689	As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2	SIGNOR-202604
P35398	O00327	1	transcriptional regulation	up-regulates quantity by expression	0.689	Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267982
P53779	O43521	1	phosphorylation	up-regulates activity	0.689	JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity.	SIGNOR-250130
Q13761	P46531	1	binding	down-regulates	0.689	To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells.	SIGNOR-188338
Q04724	Q9UJU2	1	binding	down-regulates activity	0.689	Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical.	SIGNOR-260109
P45983	Q96LC9	1	phosphorylation	up-regulates activity	0.689	Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf.	SIGNOR-250116
Q9UP38	O14640	1	binding	up-regulates activity	0.688	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-253512
P06493	P06400	1	phosphorylation	down-regulates	0.688	The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2.	SIGNOR-21564
Q13253	P43026	1	binding	down-regulates activity	0.688	Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS).	SIGNOR-252420
Q13464	P26038	1	phosphorylation	up-regulates activity	0.688	Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes.	SIGNOR-249014
P36894	Q99717	1	phosphorylation	up-regulates activity	0.688	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255261
P38435	P08709	1	carboxylation	up-regulates activity	0.688	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265919
P29350	P52333	1	dephosphorylation	up-regulates	0.688	The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase.	SIGNOR-82764
Q9BX66	P22681	1	binding	up-regulates	0.688	Cbl is recruited to the insulin receptor by interaction with the adapter protein cap, through one of three adjacent sh3 domains in the carboxy terminus of cap	SIGNOR-82283
Q14332	O75197	1	binding	up-regulates activity	0.688	Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.	SIGNOR-258968
P12931	P25963	1	phosphorylation	down-regulates quantity by destabilization	0.688	C-src phosphorylates IkappaB On tyrosine 42\|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation.	SIGNOR-60879
O15111	Q92985	1	phosphorylation	up-regulates	0.688	Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.	SIGNOR-146116
O75197	O14640	1	binding	up-regulates activity	0.688	The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.	SIGNOR-262525
P19838	P41279	1	binding	down-regulates	0.688	Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek	SIGNOR-196747
Q05397	Q9Y490	1	binding	up-regulates activity	0.688	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257731
Q96F24	Q8NEB9	1	binding	down-regulates activity	0.688	NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity.	SIGNOR-265879
Q15154	O95613	1	relocalization	up-regulates	0.688	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-95117
Q00987	Q09472	1	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
Q14164	Q92985	1	phosphorylation	up-regulates	0.687	In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3.	SIGNOR-79139

P28702

P55055

1

binding

up-regulates

0.696

We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.

SIGNOR-123094

O60674

P46527

1

phosphorylation

down-regulates activity

0.696

JAK2 phosphorylates tyrosine residue 88 (Y88) of p27(Kip1).

SIGNOR-278260

P12931

P60953

1

phosphorylation

up-regulates

0.695

Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation.

SIGNOR-118206

Q9Y6W6

Q16539

1

dephosphorylation

down-regulates

0.695

Mkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk, but not mapk/erk. p38 is a preferred substrate

SIGNOR-68983

P55072

Q96IV0

1

binding

up-regulates activity

0.695

PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.

SIGNOR-261058

P42684

P46108

1

phosphorylation

down-regulates

0.695

Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations.

SIGNOR-136958

P08581

P62993

1

binding

up-regulates activity

0.695

For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS.

SIGNOR-256261

Q96EB6

P37231

1

transcriptional regulation

down-regulates quantity by repression

0.695

Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms.

SIGNOR-268032

P51955

Q5T7B8

1

phosphorylation

up-regulates activity

0.695

Nek2 binds and phosphorylates Kif24.|We also provide evidence that Nek2 dependent phosphorylation induces a conformational change in Kif24 that promotes its activity.

SIGNOR-278413

Q6P1J9

P35222

1

binding

up-regulates

0.695

Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo

SIGNOR-146282

P33981

O43683

1

phosphorylation

up-regulates activity

0.695

After Cdk1 phosphorylates Bub1 S459, Mps1 then phosphorylates Bub1 T461 (b).

SIGNOR-278255

P08253

P07585

1

cleavage

down-regulates quantity by destabilization

0.695

Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.

SIGNOR-256350

P27361

Q16665

1

phosphorylation

up-regulates

0.695

We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_

SIGNOR-178731

Q8NFG4

Q9HB90

1

gtpase-activating protein

up-regulates activity

0.695

The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur

SIGNOR-256503

O75474

P49841

1

binding

down-regulates activity

0.695

The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation.

SIGNOR-244030

O75385

Q9C0C7

1

phosphorylation

up-regulates

0.695

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

SIGNOR-168292

P12931

P46940

1

phosphorylation

up-regulates activity

0.695

IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET.

SIGNOR-277533

Q14232

P41091

1

guanine nucleotide exchange factor

up-regulates activity

0.694

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

SIGNOR-269134

Q99836

Q13114

1

binding

up-regulates activity

0.694

Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6.

SIGNOR-256079

Q9HCE7

P36897

1

polyubiquitination

down-regulates quantity by destabilization

0.694

Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.

SIGNOR-272943

Q15628

Q13077

1

binding

up-regulates

0.694

Tradd mediates recruitment of traf1/2

SIGNOR-73913

P19793

P55055

1

binding

up-regulates

0.694

We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.

SIGNOR-123091

P25445

Q99683

1

binding

up-regulates

0.694

Ask1 binds fas

SIGNOR-109676

P27361

P49815

1

phosphorylation

down-regulates activity

0.694

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-249457

O94856

Q01484

1

relocalization

up-regulates quantity

0.694

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-266716

P22681

P27986

1

ubiquitination

down-regulates

0.694

Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.

SIGNOR-110060

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

P56211

Q66LE6

1

binding

down-regulates activity

0.694

We identified cyclic adenosine monophosphateregulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.

SIGNOR-243731

P54646

Q8N122

1

phosphorylation

down-regulates activity

0.693

These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK

SIGNOR-163463

P35240

Q9NRM7

1

binding

up-regulates

0.693

As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2

SIGNOR-202607

P67775

Q13188

1

dephosphorylation

down-regulates

0.693

Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.

SIGNOR-201266

P34130

P04629

1

binding

up-regulates

0.693

Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.

SIGNOR-85117

P49674

O14641

1

phosphorylation

up-regulates

0.693

We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle

SIGNOR-197555

Q9NQS7

O14965

2

binding

up-regulates activity

0.693

INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop

SIGNOR-252048

O14965

Q9NQS7

2

phosphorylation

up-regulates activity

0.693

INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop

SIGNOR-252047

Q86YT6

P78504

1

ubiquitination

up-regulates activity

0.693

Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum.

SIGNOR-97388

O60674

O14744

1

phosphorylation

down-regulates

0.693

Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity

SIGNOR-171994

P27361

P35236

1

phosphorylation

up-regulates activity

0.693

First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|

SIGNOR-249475

Q6UXX9

O75473

1

binding

up-regulates

0.693

Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation

SIGNOR-174532

P28482

P30041

1

phosphorylation

up-regulates

0.693

These results show that the mapks can mediate phosphorylation of prdx6 at thr-177 with a consequent marked increase in its aipla(2) activity.

SIGNOR-183379

Q9Y3M2

P35222

1

binding

down-regulates

0.693

Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin.

SIGNOR-100835

Q12770

P36956

1

binding

up-regulates activity

0.692

Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis.

SIGNOR-256210

P56524

Q14814

1

binding

down-regulates

0.692

We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.

SIGNOR-76237

O14920

O43524

1

phosphorylation

down-regulates

0.692

Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway

SIGNOR-124207

P17252

O14939

1

phosphorylation

up-regulates

0.692

The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity

SIGNOR-138355

P62834

P15056

1

binding

up-regulates activity

0.692

Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis).

SIGNOR-276608

O75962

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.692

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-260579

P06239

P07766

1

phosphorylation

up-regulates activity

0.692

Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways.

SIGNOR-251369

P01303

P50391

1

binding

up-regulates

0.692

Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.

SIGNOR-29633

P04628

O60353

1

binding

up-regulates activity

0.692

Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway.

SIGNOR-198846

Q04206

P05231

1

transcriptional regulation

up-regulates quantity by expression

0.692

Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation

SIGNOR-251737

P15498

P22681

1

binding

up-regulates

0.692

Hese data imply that c-cbl is a molecular adapter that regulates the function of vav

SIGNOR-49188

P30304

P20248

1

dephosphorylation

up-regulates activity

0.692

Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1 [4,5] .

SIGNOR-277136

Q96SN8

Q96MT8

1

relocalization

up-regulates activity

0.692

Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.

SIGNOR-271722

Q9NRF2

O60674

1

binding

up-regulates activity

0.692

The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex

SIGNOR-253078

Q8IU81

P14316

1

binding

up-regulates activity

0.692

We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.

SIGNOR-224045

P18031

P09619

1

dephosphorylation

down-regulates

0.691

Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.

SIGNOR-179064

Q13705

P36896

1

phosphorylation

up-regulates activity

0.691

Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.

SIGNOR-235146

P04637

Q16611

1

binding

up-regulates

0.691

P53 interacts with the pro-apoptotic mitochondrial membrane protein bak

SIGNOR-124122

P98170

P60484

1

ubiquitination

down-regulates quantity

0.691

Finally, we found that XIAP can directly ubiquitinate PTEN in vitro.|Overexpression of XIAP induces polyubiquitination of PTEN and proteasome dependent decrease of PTEN protein levels.

SIGNOR-278751

P49137

P16220

1

phosphorylation

up-regulates activity

0.691

Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2.

SIGNOR-166619

P49841

P16220

1

phosphorylation

up-regulates activity

0.691

GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant

SIGNOR-251233

P46020

Q16816

1

binding

down-regulates activity

0.691

Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.

SIGNOR-267405

Q9H4P4

P21860

1

polyubiquitination

down-regulates quantity by destabilization

0.691

Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3

SIGNOR-272599

Q9UQ13

O14807

1

binding

up-regulates

0.69

Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf.

SIGNOR-77082

Q08881

P10747

1

phosphorylation

up-regulates

0.69

We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor

SIGNOR-198747

O75582

P18846

1

phosphorylation

up-regulates activity

0.69

Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts

SIGNOR-249144

Q8TD19

Q9HC98

1

phosphorylation

up-regulates activity

0.69

Nercc1/nek9 activates the nek6 and nek7 kinases. Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant nek6 at ser206 in vitro concomitant with 20-25-fold activation of nek6 activity.

SIGNOR-102996

Q13705

P84022

1

phosphorylation

up-regulates activity

0.69

It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains

SIGNOR-254985

Q8WWW0

P01116

1

binding

up-regulates activity

0.69

NORE1A can bind K-Ras.GTP through its RA domain and regulate the proapoptotic activity of MST1/2 kinases

SIGNOR-249586

Q13418

P49841

1

phosphorylation

down-regulates activity

0.69

ILK can also directly phosphorylates GSK-3\u03b2 at Ser 9, inactivate it, and lead to activation of some transcription factors [ ].|ILK knockdown activates GSK-3beta.

SIGNOR-278252

P35222

P15884

1

binding

up-regulates activity

0.69

beta-catenin interacts with the TCF/Lef family transcription factors.

SIGNOR-178042

Q05397

O00401

1

phosphorylation

up-regulates activity

0.69

In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.

SIGNOR-278977

Q16659

Q8IW41

1

phosphorylation

up-regulates activity

0.69

ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5.

SIGNOR-279073

O14641

O75581

1

binding

up-regulates activity

0.69

Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction.

SIGNOR-66362

Q92793

Q06413

1

binding

up-regulates

0.689

The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.

SIGNOR-83843

P35240

O95835

1

binding

up-regulates

0.689

As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2

SIGNOR-202604

P35398

O00327

1

transcriptional regulation

up-regulates quantity by expression

0.689

Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.

SIGNOR-267982

P53779

O43521

1

phosphorylation

up-regulates activity

0.689

JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity.

SIGNOR-250130

Q13761

P46531

1

binding

down-regulates

0.689

To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells.

SIGNOR-188338

Q04724

Q9UJU2

1

binding

down-regulates activity

0.689

Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical.

SIGNOR-260109

P45983

Q96LC9

1

phosphorylation

up-regulates activity

0.689

Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf.

SIGNOR-250116

Q9UP38

O14640

1

binding

up-regulates activity

0.688

When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.

SIGNOR-253512

P06493

P06400

1

phosphorylation

down-regulates

0.688

The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2.

SIGNOR-21564

Q13253

P43026

1

binding

down-regulates activity

0.688

Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS).

SIGNOR-252420

Q13464

P26038

1

phosphorylation

up-regulates activity

0.688

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

SIGNOR-249014

P36894

Q99717

1

phosphorylation

up-regulates activity

0.688

Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.

SIGNOR-255261

P38435

P08709

1

carboxylation

up-regulates activity

0.688

Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.

SIGNOR-265919

P29350

P52333

1

dephosphorylation

up-regulates

0.688

The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase.

SIGNOR-82764

Q9BX66

P22681

1

binding

up-regulates

0.688

Cbl is recruited to the insulin receptor by interaction with the adapter protein cap, through one of three adjacent sh3 domains in the carboxy terminus of cap

SIGNOR-82283

Q14332

O75197

1

binding

up-regulates activity

0.688

Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.

SIGNOR-258968

P12931

P25963

1

phosphorylation

down-regulates quantity by destabilization

0.688

C-src phosphorylates IkappaB On tyrosine 42|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation.

SIGNOR-60879

O15111

Q92985

1

phosphorylation

up-regulates

0.688

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

SIGNOR-146116

O75197

O14640

1

binding

up-regulates activity

0.688

The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.

SIGNOR-262525

P19838

P41279

1

binding

down-regulates

0.688

Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek

SIGNOR-196747

Q05397

Q9Y490

1

binding

up-regulates activity

0.688

Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.

SIGNOR-257731

Q96F24

Q8NEB9

1

binding

down-regulates activity

0.688

NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity.

SIGNOR-265879

Q15154

O95613

1

relocalization

up-regulates

0.688

Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome

SIGNOR-95117

Q00987

Q09472

1

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

Q14164

Q92985

1

phosphorylation

up-regulates

0.687

In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3.

SIGNOR-79139