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
Q12913	P36888	1	dephosphorylation	down-regulates activity	0.49	Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.\|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.	SIGNOR-277092
Q6ZVD8	P23443	1	dephosphorylation	down-regulates activity	0.49	We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro	SIGNOR-248247
Q9BXH1	Q07812	1	relocalization	up-regulates	0.49	Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.	SIGNOR-185671
P06493	P30622	1	phosphorylation	up-regulates activity	0.49	Cdc2 phosphorylates T287\|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. \|These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression.	SIGNOR-275470
Q12913	P00533	1	dephosphorylation	up-regulates quantity by stabilization	0.49	We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex\|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173	SIGNOR-248697
Q3KRB8	P60953	1	gtpase-activating protein	down-regulates activity	0.49	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-260468
Q86XK2	P41182	1	binding	down-regulates	0.49	Fbxo11 targets bcl6 for degradation	SIGNOR-177652
P16234	P12931	1	phosphorylation	up-regulates activity	0.49	The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.	SIGNOR-247984
Q92793	Q13351	1	acetylation	up-regulates activity	0.49	EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain.	SIGNOR-251826
Q16566	P16949	1	phosphorylation	down-regulates	0.49	Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr.	SIGNOR-34743
P28482	Q92574	1	phosphorylation	down-regulates	0.49	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 signalin.	SIGNOR-157162
P45984	P19419	1	phosphorylation	up-regulates activity	0.49	However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.	SIGNOR-247062
O14757	Q53H47	1	phosphorylation	down-regulates activity	0.49	We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.	SIGNOR-273610
P30556	O95837	1	binding	up-regulates activity	0.49	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-257133
P06493	O95239	1	phosphorylation	up-regulates activity	0.489	Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.	SIGNOR-265994
P07339	P05067	1	cleavage	down-regulates quantity by destabilization	0.489	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. \| two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261767
P06493	Q92574	1	phosphorylation	down-regulates	0.489	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-118584
P06241	Q16539	1	phosphorylation	up-regulates	0.489	T cell src family kinases and zap70 activate p38 by phosphorylating tyr323.	SIGNOR-134293
P54646	Q53ET0	1	phosphorylation	down-regulates	0.489	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-142211
P19784	Q16543	1	phosphorylation	up-regulates activity	0.489	Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. \| In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site.	SIGNOR-250982
Q8TCY5	P32245	1	binding	down-regulates activity	0.489	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252362
Q8IWT3	O15392	1	ubiquitination	down-regulates quantity	0.489	CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7.\|Together, these results demonstrate the specificity of survivin ubiquitylation by CUL9 E3 ligase complex.	SIGNOR-278808
P28482	P41182	1	phosphorylation	down-regulates	0.489	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58481
P78347	P22415	1	binding	up-regulates activity	0.489	TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription	SIGNOR-268538
P78536	P01135	1	cleavage	up-regulates activity	0.489	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259841
P35869	Q16678	1	transcriptional regulation	up-regulates quantity by expression	0.489	The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 .	SIGNOR-253642
Q96Q05	O14920	1	binding	up-regulates activity	0.489	We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.	SIGNOR-269673
P34947	P30411	1	phosphorylation	down-regulates activity	0.489	Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251208
O15392	P42574	1	binding	down-regulates	0.489	Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21.	SIGNOR-72882
P12931	P10398	1	phosphorylation	up-regulates activity	0.489	A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation	SIGNOR-236459
P35555	P01137	1	binding	up-regulates quantity	0.489	We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling.	SIGNOR-251888
Q9BZY9	Q96P20	1	ubiquitination	down-regulates quantity by destabilization	0.489	Taken together, these data indicated that TRIM31 directly induced the K48-linked ubiquitination of NLRP3 through its E3 ligase activity.\|Taken together, these results indicated that TRIM31 could promote proteasomal degradation of NLRP3.	SIGNOR-278603
P13500	P51679	1	binding	up-regulates activity	0.489	CCR2 and CCR4 are two cell surface receptors that bind CCL2	SIGNOR-237555
P54829	Q16539	1	binding	up-regulates	0.489	First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a.	SIGNOR-194829
Q06124	Q14511	1	dephosphorylation	down-regulates activity	0.488	In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.\|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.	SIGNOR-277083
P18825	P08754	1	binding	up-regulates activity	0.488	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-256842
O15297	Q13315	1	dephosphorylation	down-regulates	0.488	The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity.	SIGNOR-185135
P50570	P15498	1	binding	up-regulates quantity by stabilization	0.488	Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability.	SIGNOR-259080
P24941	Q15796	1	phosphorylation	down-regulates activity	0.488	Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.\|Moreover, CDK2 is the predominant cyclin-dependent kinase that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.	SIGNOR-279678
P26358	Q9BZS1	1	transcriptional regulation	down-regulates quantity by repression	0.488	Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)	SIGNOR-269053
Q15831	Q9Y2K2	1	phosphorylation	up-regulates	0.488	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122835
Q13950	P10451	1	transcriptional regulation	up-regulates quantity	0.488	Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.	SIGNOR-245336
P16220	P23560	1	transcriptional regulation	up-regulates quantity	0.488	Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF.	SIGNOR-265062
Q15831	P38936	1	phosphorylation	down-regulates activity	0.488	Mass spectrometry analysis of the phosphorylated CDKN1A identified Thr80 as the residue phosphorylated by LKB1 in vitro (Figure 4A and S5A).\|UVB induced phosphorylation of LKB1 T366 mediates CDKN1A degradation.	SIGNOR-278253
P51955	P36873	1	phosphorylation	down-regulates	0.488	Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity.	SIGNOR-78603
P0DP24	Q8N5S9	1	binding	up-regulates	0.488	The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases	SIGNOR-266328
P49841	P84022	1	phosphorylation	down-regulates quantity by destabilization	0.488	Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.	SIGNOR-160318
Q86UX7	Q8WUP2	1	binding	up-regulates activity	0.488	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.	SIGNOR-266104
Q03164	Q9H7Z6	1	binding	up-regulates	0.488	Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome	SIGNOR-138245
Q8NG27	Q15910	1	ubiquitination	down-regulates quantity by destabilization	0.488	Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2	SIGNOR-255664
P42226	P42224	1	binding	down-regulates activity	0.488	STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site	SIGNOR-249552
Q13882	P22681	1	phosphorylation	down-regulates activity	0.488	Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl.	SIGNOR-279348
Q04323	Q96IV0	1	binding	up-regulates activity	0.488	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-261060
P19544	O60500	1	transcriptional regulation	up-regulates quantity by expression	0.487	The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner	SIGNOR-252299
Q16236	P15559	1	transcriptional regulation	up-regulates quantity by expression	0.487	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256275
Q04759	Q9UEW8	1	phosphorylation	up-regulates activity	0.487	Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK.	SIGNOR-276007
Q99683	Q969S3	1	phosphorylation	up-regulates	0.487	Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.	SIGNOR-175113
P49841	Q9Y6H5	1	phosphorylation	down-regulates	0.487	Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1	SIGNOR-140609
O96017	Q01094	1	phosphorylation	up-regulates quantity by stabilization	0.487	We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage	SIGNOR-100898
O60315	P12830	1	transcriptional regulation	down-regulates quantity by repression	0.487	SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation).	SIGNOR-268950
P63211	P48736	1	binding	up-regulates	0.487	Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma.	SIGNOR-96831
P06241	Q14643	1	phosphorylation	up-regulates	0.487	We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm).	SIGNOR-121795
Q13627	P16220	1	phosphorylation	up-regulates activity	0.487	Regarding to the functional role of Dyrk1A, active Dyrk1A phosphorylates the transcription factor cAMP response element -binding protein (CREB), which subsequently leads to the stimulation of cAMP response element-mediated gene transcription during neuronal differentiation ( ).	SIGNOR-279989
P78317	P29590	1	polyubiquitination	down-regulates quantity by destabilization	0.487	Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.	SIGNOR-272884
O43293	P24844	1	phosphorylation	up-regulates	0.487	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188789
Q16236	Q5RD31	1	transcriptional regulation	up-regulates quantity by expression	0.487	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.NFE2L2-mediated upregulation of NQO1 is implicated in promoting resistance to ferroptosis inducers, such as erastin and sorafenib, in HCC cells	SIGNOR-279860
P78411	Q9NZV8	1	transcriptional regulation	down-regulates quantity by repression	0.487	Irx5 Directly Represses the Kcnd2 Promoter	SIGNOR-266045
O14901	Q96ST3	1	binding	up-regulates activity	0.487	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222344
P30304	P14618	1	dephosphorylation	up-regulates activity	0.487	Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.\|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.	SIGNOR-276967
P34981	P30679	1	binding	up-regulates activity	0.487	Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation	SIGNOR-278132
Q13107	O43395	1	deubiquitination	down-regulates activity	0.487	Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site.	SIGNOR-271975
Q8NES3	P78504	1	binding	down-regulates	0.486	Although jagged1-induced signaling was suppressed by lfng and mfng	SIGNOR-131560
P12270	Q9Y6D9	1	binding	up-regulates	0.486	Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20).	SIGNOR-181918
Q5JUK2	Q68G74	1	transcriptional regulation	up-regulates quantity by expression	0.486	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266076
Q05086	P54725	1	polyubiquitination	down-regulates quantity by destabilization	0.486	Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP. E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.	SIGNOR-272550
Q16650	Q8TBJ5	1	transcriptional regulation	down-regulates quantity by repression	0.486	We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.\|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene.	SIGNOR-268967
P35637	P43243	1	relocalization	up-regulates activity	0.486	Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates.	SIGNOR-262822
P31749	Q07812	1	phosphorylation	down-regulates activity	0.486	Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members	SIGNOR-252538
Q9UHF4	P23458	1	binding	up-regulates	0.486	Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain.	SIGNOR-124486
P17612	P03372	1	phosphorylation	down-regulates	0.486	Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha	SIGNOR-63984
P63096	P12931	1	binding	up-regulates activity	0.486	Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src	SIGNOR-256526
P53350	Q9Y2T1	1	phosphorylation	up-regulates activity	0.486	Plk1 phosphorylates axin2 at Ser311.	SIGNOR-277180
O43597	Q13191	1	binding	down-regulates	0.486	One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis.	SIGNOR-83507
P31749	P04150	1	phosphorylation	down-regulates	0.486	Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus	SIGNOR-252543
P17612	P13569	1	phosphorylation	up-regulates	0.485	Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response.	SIGNOR-21312
Q9Y243	P29474	1	phosphorylation	up-regulates activity	0.485	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251626
Q96F44	Q99453	1	ubiquitination	down-regulates	0.485	The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.	SIGNOR-195878
P49841	P36956	1	phosphorylation	down-regulates quantity by destabilization	0.485	Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.	SIGNOR-236667
O43464	Q15121	1	binding	down-regulates	0.485	Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15	SIGNOR-126966
Q99873	P35637	1	methylation	down-regulates activity	0.485	PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis.	SIGNOR-262274
Q96RI0	Q03113	1	binding	up-regulates	0.485	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).	SIGNOR-196012
P27448	P30307	1	phosphorylation	down-regulates activity	0.485	C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function.	SIGNOR-250176
O15111	P35222	1	phosphorylation	up-regulates quantity	0.485	Interestingly, while IKK2 negatively regulates beta-catenin stability similar to GSK3beta, IKK1 seems to increase beta-catenin protein level and downstream signal, such as cyclin D1 transcription.\|These results suggested IKK1 may phosphorylate beta-catenin at different residues and protect it from ubiquitination mediated degradation.	SIGNOR-280230
P52306	P63000	1	binding	up-regulates	0.485	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171418
P31749	Q99623	1	binding	down-regulates	0.485	Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation	SIGNOR-252541
P68400	P27695	1	phosphorylation	up-regulates activity	0.485	Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1.	SIGNOR-250825
Q15831	Q8TDC3	1	phosphorylation	up-regulates	0.485	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122413
P34981	P29992	1	binding	up-regulates activity	0.485	Binding of TRH to TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.	SIGNOR-267201
Q15303	P42338	1	binding	up-regulates	0.485	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146882
P29323	O94989	1	phosphorylation	down-regulates quantity by destabilization	0.485	We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361	SIGNOR-262864

Q12913

P36888

1

dephosphorylation

down-regulates activity

0.49

Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.

SIGNOR-277092

Q6ZVD8

P23443

1

dephosphorylation

down-regulates activity

0.49

We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro

SIGNOR-248247

Q9BXH1

Q07812

1

relocalization

up-regulates

0.49

Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.

SIGNOR-185671

P06493

P30622

1

phosphorylation

up-regulates activity

0.49

Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression.

SIGNOR-275470

Q12913

P00533

1

dephosphorylation

up-regulates quantity by stabilization

0.49

We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173

SIGNOR-248697

Q3KRB8

P60953

1

gtpase-activating protein

down-regulates activity

0.49

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-260468

Q86XK2

P41182

1

binding

down-regulates

0.49

Fbxo11 targets bcl6 for degradation

SIGNOR-177652

P16234

P12931

1

phosphorylation

up-regulates activity

0.49

The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.

SIGNOR-247984

Q92793

Q13351

1

acetylation

up-regulates activity

0.49

EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain.

SIGNOR-251826

Q16566

P16949

1

phosphorylation

down-regulates

0.49

Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr.

SIGNOR-34743

P28482

Q92574

1

phosphorylation

down-regulates

0.49

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 signalin.

SIGNOR-157162

P45984

P19419

1

phosphorylation

up-regulates activity

0.49

However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.

SIGNOR-247062

O14757

Q53H47

1

phosphorylation

down-regulates activity

0.49

We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.

SIGNOR-273610

P30556

O95837

1

binding

up-regulates activity

0.49

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-257133

P06493

O95239

1

phosphorylation

up-regulates activity

0.489

Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.

SIGNOR-265994

P07339

P05067

1

cleavage

down-regulates quantity by destabilization

0.489

The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.

SIGNOR-261767

P06493

Q92574

1

phosphorylation

down-regulates

0.489

Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex

SIGNOR-118584

P06241

Q16539

1

phosphorylation

up-regulates

0.489

T cell src family kinases and zap70 activate p38 by phosphorylating tyr323.

SIGNOR-134293

P54646

Q53ET0

1

phosphorylation

down-regulates

0.489

Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2

SIGNOR-142211

P19784

Q16543

1

phosphorylation

up-regulates activity

0.489

Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site.

SIGNOR-250982

Q8TCY5

P32245

1

binding

down-regulates activity

0.489

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.

SIGNOR-252362

Q8IWT3

O15392

1

ubiquitination

down-regulates quantity

0.489

CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7.|Together, these results demonstrate the specificity of survivin ubiquitylation by CUL9 E3 ligase complex.

SIGNOR-278808

P28482

P41182

1

phosphorylation

down-regulates

0.489

Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.

SIGNOR-58481

P78347

P22415

1

binding

up-regulates activity

0.489

TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription

SIGNOR-268538

P78536

P01135

1

cleavage

up-regulates activity

0.489

ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF

SIGNOR-259841

P35869

Q16678

1

transcriptional regulation

up-regulates quantity by expression

0.489

The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 .

SIGNOR-253642

Q96Q05

O14920

1

binding

up-regulates activity

0.489

We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.

SIGNOR-269673

P34947

P30411

1

phosphorylation

down-regulates activity

0.489

Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.

SIGNOR-251208

O15392

P42574

1

binding

down-regulates

0.489

Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21.

SIGNOR-72882

P12931

P10398

1

phosphorylation

up-regulates activity

0.489

A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation

SIGNOR-236459

P35555

P01137

1

binding

up-regulates quantity

0.489

We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling.

SIGNOR-251888

Q9BZY9

Q96P20

1

ubiquitination

down-regulates quantity by destabilization

0.489

Taken together, these data indicated that TRIM31 directly induced the K48-linked ubiquitination of NLRP3 through its E3 ligase activity.|Taken together, these results indicated that TRIM31 could promote proteasomal degradation of NLRP3.

SIGNOR-278603

P13500

P51679

1

binding

up-regulates activity

0.489

CCR2 and CCR4 are two cell surface receptors that bind CCL2

SIGNOR-237555

P54829

Q16539

1

binding

up-regulates

0.489

First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a.

SIGNOR-194829

Q06124

Q14511

1

dephosphorylation

down-regulates activity

0.488

In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.

SIGNOR-277083

P18825

P08754

1

binding

up-regulates activity

0.488

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-256842

O15297

Q13315

1

dephosphorylation

down-regulates

0.488

The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity.

SIGNOR-185135

P50570

P15498

1

binding

up-regulates quantity by stabilization

0.488

Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability.

SIGNOR-259080

P24941

Q15796

1

phosphorylation

down-regulates activity

0.488

Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.|Moreover, CDK2 is the predominant cyclin-dependent kinase that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.

SIGNOR-279678

P26358

Q9BZS1

1

transcriptional regulation

down-regulates quantity by repression

0.488

Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)

SIGNOR-269053

Q15831

Q9Y2K2

1

phosphorylation

up-regulates

0.488

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122835

Q13950

P10451

1

transcriptional regulation

up-regulates quantity

0.488

Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.

SIGNOR-245336

P16220

P23560

1

transcriptional regulation

up-regulates quantity

0.488

Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF.

SIGNOR-265062

Q15831

P38936

1

phosphorylation

down-regulates activity

0.488

Mass spectrometry analysis of the phosphorylated CDKN1A identified Thr80 as the residue phosphorylated by LKB1 in vitro (Figure 4A and S5A).|UVB induced phosphorylation of LKB1 T366 mediates CDKN1A degradation.

SIGNOR-278253

P51955

P36873

1

phosphorylation

down-regulates

0.488

Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity.

SIGNOR-78603

P0DP24

Q8N5S9

1

binding

up-regulates

0.488

The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases

SIGNOR-266328

P49841

P84022

1

phosphorylation

down-regulates quantity by destabilization

0.488

Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.

SIGNOR-160318

Q86UX7

Q8WUP2

1

binding

up-regulates activity

0.488

Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.

SIGNOR-266104

Q03164

Q9H7Z6

1

binding

up-regulates

0.488

Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome

SIGNOR-138245

Q8NG27

Q15910

1

ubiquitination

down-regulates quantity by destabilization

0.488

Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2

SIGNOR-255664

P42226

P42224

1

binding

down-regulates activity

0.488

STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site

SIGNOR-249552

Q13882

P22681

1

phosphorylation

down-regulates activity

0.488

Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl.

SIGNOR-279348

Q04323

Q96IV0

1

binding

up-regulates activity

0.488

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-261060

P19544

O60500

1

transcriptional regulation

up-regulates quantity by expression

0.487

The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner

SIGNOR-252299

Q16236

P15559

1

transcriptional regulation

up-regulates quantity by expression

0.487

In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).

SIGNOR-256275

Q04759

Q9UEW8

1

phosphorylation

up-regulates activity

0.487

Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK.

SIGNOR-276007

Q99683

Q969S3

1

phosphorylation

up-regulates

0.487

Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.

SIGNOR-175113

P49841

Q9Y6H5

1

phosphorylation

down-regulates

0.487

Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1

SIGNOR-140609

O96017

Q01094

1

phosphorylation

up-regulates quantity by stabilization

0.487

We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage

SIGNOR-100898

O60315

P12830

1

transcriptional regulation

down-regulates quantity by repression

0.487

SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation).

SIGNOR-268950

P63211

P48736

1

binding

up-regulates

0.487

Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma.

SIGNOR-96831

P06241

Q14643

1

phosphorylation

up-regulates

0.487

We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm).

SIGNOR-121795

Q13627

P16220

1

phosphorylation

up-regulates activity

0.487

Regarding to the functional role of Dyrk1A, active Dyrk1A phosphorylates the transcription factor cAMP response element -binding protein (CREB), which subsequently leads to the stimulation of cAMP response element-mediated gene transcription during neuronal differentiation ( ).

SIGNOR-279989

P78317

P29590

1

polyubiquitination

down-regulates quantity by destabilization

0.487

Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.

SIGNOR-272884

O43293

P24844

1

phosphorylation

up-regulates

0.487

More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.

SIGNOR-188789

Q16236

Q5RD31

1

transcriptional regulation

up-regulates quantity by expression

0.487

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.NFE2L2-mediated upregulation of NQO1 is implicated in promoting resistance to ferroptosis inducers, such as erastin and sorafenib, in HCC cells

SIGNOR-279860

P78411

Q9NZV8

1

transcriptional regulation

down-regulates quantity by repression

0.487

Irx5 Directly Represses the Kcnd2 Promoter

SIGNOR-266045

O14901

Q96ST3

1

binding

up-regulates activity

0.487

detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.

SIGNOR-222344

P30304

P14618

1

dephosphorylation

up-regulates activity

0.487

Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.

SIGNOR-276967

P34981

P30679

1

binding

up-regulates activity

0.487

Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation

SIGNOR-278132

Q13107

O43395

1

deubiquitination

down-regulates activity

0.487

Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site.

SIGNOR-271975

Q8NES3

P78504

1

binding

down-regulates

0.486

Although jagged1-induced signaling was suppressed by lfng and mfng

SIGNOR-131560

P12270

Q9Y6D9

1

binding

up-regulates

0.486

Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20).

SIGNOR-181918

Q5JUK2

Q68G74

1

transcriptional regulation

up-regulates quantity by expression

0.486

Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.

SIGNOR-266076

Q05086

P54725

1

polyubiquitination

down-regulates quantity by destabilization

0.486

Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP. E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.

SIGNOR-272550

Q16650

Q8TBJ5

1

transcriptional regulation

down-regulates quantity by repression

0.486

We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene.

SIGNOR-268967

P35637

P43243

1

relocalization

up-regulates activity

0.486

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

SIGNOR-262822

P31749

Q07812

1

phosphorylation

down-regulates activity

0.486

Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members

SIGNOR-252538

Q9UHF4

P23458

1

binding

up-regulates

0.486

Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain.

SIGNOR-124486

P17612

P03372

1

phosphorylation

down-regulates

0.486

Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha

SIGNOR-63984

P63096

P12931

1

binding

up-regulates activity

0.486

Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src

SIGNOR-256526

P53350

Q9Y2T1

1

phosphorylation

up-regulates activity

0.486

Plk1 phosphorylates axin2 at Ser311.

SIGNOR-277180

O43597

Q13191

1

binding

down-regulates

0.486

One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis.

SIGNOR-83507

P31749

P04150

1

phosphorylation

down-regulates

0.486

Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus

SIGNOR-252543

P17612

P13569

1

phosphorylation

up-regulates

0.485

Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response.

SIGNOR-21312

Q9Y243

P29474

1

phosphorylation

up-regulates activity

0.485

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251626

Q96F44

Q99453

1

ubiquitination

down-regulates

0.485

The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.

SIGNOR-195878

P49841

P36956

1

phosphorylation

down-regulates quantity by destabilization

0.485

Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.

SIGNOR-236667

O43464

Q15121

1

binding

down-regulates

0.485

Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15

SIGNOR-126966

Q99873

P35637

1

methylation

down-regulates activity

0.485

PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis.

SIGNOR-262274

Q96RI0

Q03113

1

binding

up-regulates

0.485

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

SIGNOR-196012

P27448

P30307

1

phosphorylation

down-regulates activity

0.485

C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function.

SIGNOR-250176

O15111

P35222

1

phosphorylation

up-regulates quantity

0.485

Interestingly, while IKK2 negatively regulates beta-catenin stability similar to GSK3beta, IKK1 seems to increase beta-catenin protein level and downstream signal, such as cyclin D1 transcription.|These results suggested IKK1 may phosphorylate beta-catenin at different residues and protect it from ubiquitination mediated degradation.

SIGNOR-280230

P52306

P63000

1

binding

up-regulates

0.485

Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob

SIGNOR-171418

P31749

Q99623

1

binding

down-regulates

0.485

Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation

SIGNOR-252541

P68400

P27695

1

phosphorylation

up-regulates activity

0.485

Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1.

SIGNOR-250825

Q15831

Q8TDC3

1

phosphorylation

up-regulates

0.485

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122413

P34981

P29992

1

binding

up-regulates activity

0.485

Binding of TRH to TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.

SIGNOR-267201

Q15303

P42338

1

binding

up-regulates

0.485

Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.

SIGNOR-146882

P29323

O94989

1

phosphorylation

down-regulates quantity by destabilization

0.485

We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361

SIGNOR-262864