GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P09471	P30542	2	binding	up-regulates activity	0.39	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-256976
Q12772	Q14703	0	cleavage	up-regulates activity	0.594	We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2	SIGNOR-267496
O95714	P38398	1	ubiquitination	down-regulates quantity by destabilization	0.561	HERC2 ubiquitinates BRCA1; this reaction depends on Cys(4762) of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1.\|Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G(2)-M checkpoint activity.	SIGNOR-278813
P46531	Q9NWT6	0	hydroxylation	down-regulates	0.55	We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation.	SIGNOR-161057
P23769	P10828	2	binding	down-regulates activity	0.2	We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2.	SIGNOR-267256
P07196	P17612	0	phosphorylation	down-regulates activity	0.2	Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L.	SIGNOR-252401
P01266	Q06710	0	transcriptional regulation	up-regulates quantity by expression	0.458	The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression.	SIGNOR-251998
Q13683	P15173	0	transcriptional regulation	up-regulates quantity by expression	0.283	Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.	SIGNOR-241521
P43405	Q13191	0	ubiquitination	down-regulates quantity	0.696	In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.\|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.	SIGNOR-278754
Q96PN8	O15530	0	phosphorylation	up-regulates activity	0.261	We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.	SIGNOR-260786
P05019	P42229	0	transcriptional regulation	up-regulates quantity by expression	0.433	Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α	SIGNOR-251743
Q99759	P53805	1	phosphorylation	up-regulates	0.448	Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation	SIGNOR-102294
P49841	Q14449	1	phosphorylation	down-regulates activity	0.323	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor\| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264867
P49137	P04792	1	phosphorylation	down-regulates	0.809	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-94021
Q9NP62	Q9P0U3	0	desumoylation	up-regulates activity	0.468	We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.	SIGNOR-262681
Q92630	P46531	1	phosphorylation	down-regulates quantity by destabilization	0.288	We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism.	SIGNOR-279035
P48730	O43312	1	phosphorylation	down-regulates quantity by destabilization	0.327	Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.	SIGNOR-276611
P06493	P23769	1	phosphorylation	down-regulates quantity by destabilization	0.355	GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1).	SIGNOR-276884
Q9H2X6	Q92793	1	phosphorylation	up-regulates activity	0.424	Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CREB-binding protein.\|We show that HIPK2 interacts with and phosphorylates several regions of CBP.	SIGNOR-279191
Q05655	O00429	1	phosphorylation	up-regulates	0.2	Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation.	SIGNOR-153148
Q14185	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.735	We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.	SIGNOR-266822
Q92914	Q99250	2	binding	down-regulates activity	0.252	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253430
P12644	Q13253	2	binding	down-regulates	0.814	Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides	SIGNOR-100660
Q08999	P67775	0	dephosphorylation	up-regulates	0.581	Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation.	SIGNOR-129752
P57078	Q13489	0	polyubiquitination	up-regulates activity	0.355	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.	SIGNOR-272709
P06493	Q9UPT9	1	phosphorylation	up-regulates activity	0.47	On the other hand, CDK1 enhances USP22 activity to stabilize CCNB1 during the G2/M phase.\|Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1.	SIGNOR-278241
O60502	P11413	1	deglycosylation	down-regulates activity	0.2	O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth\|O-GlcNAcylation of G6PD activates enzyme activity\|G6PD is dynamically modified by O-GlcNAc at serine 84\|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.	SIGNOR-267605
Q9UQB3	P12830	2	binding	up-regulates quantity by stabilization	0.447	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252134
P38484	P01579	2	binding	up-regulates	0.649	Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction	SIGNOR-31013
Q969H0	Q8WUJ0	2	binding	down-regulates activity	0.346	STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients,	SIGNOR-251663
Q14493	P62807	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265377
O43602	P49841	0	phosphorylation	up-regulates activity	0.271	Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact.	SIGNOR-170755
P23470	P24941	1	dephosphorylation	down-regulates activity	0.298	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254695
P08151	P08631	0	phosphorylation	up-regulates activity	0.299	These results suggest that the interaction between Gli1 and Hck or the phosphorylation of Gli1 by Hck disrupts Sufu-Gli1 interaction.\|We showed that tyrosine kinase Hck activates Gli1 and the kinase activity is required for its maximum effect.	SIGNOR-279374
Q13164	Q14814	1	phosphorylation	up-regulates	0.705	Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b. the sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236041
P46108	P52564	0	phosphorylation	up-regulates	0.2	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily.	SIGNOR-42384
Q9Y243	P04792	1	phosphorylation	down-regulates	0.286	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186780
P48050	P17252	0	phosphorylation	down-regulates activity	0.2	These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3.	SIGNOR-275965
O43592	P62826	2	binding	up-regulates activity	0.815	The first step in export appears to be the formation of a trimeric tRNA/exportin-t/RanGTP complex. tRNA and RanGTP bind to exportin-t in a highly cooperative manner: tRNA increases the affinity of exportin-t for RanGTP apparently 300-fold (Figure 5A); conversely, RanGTP has to increase the affinity of exportin-t for tRNA by the same factor. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus	SIGNOR-261392
P51812	P19634	1	phosphorylation	up-regulates activity	0.414	In pressured arteries, RSK2 dependent activation of NHE-1 was associated with increased intracellular Ca 2+ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses.\|Together, these data indicate that Ser 703 in NHE-1 is phosphorylated by RSK2, that RSK2 is associated with NHE-1, and that the time course of NHE-1 phosphorylation in response to intraluminal pressure is fast enough for this phosphorylation event to contribute to myogenic vasoconstriction.	SIGNOR-280119
P62136	P46937	1	dephosphorylation	up-regulates activity	0.668	In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.\|PP1A dephosphorylates endogenous YAP2 at serine 127.	SIGNOR-276999
Q9H0H5	P53350	0	phosphorylation	up-regulates	0.638	Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.	SIGNOR-185758
P01106	P62714	0	dephosphorylation	down-regulates	0.276	Phosphorylation at ser-62 by pro-directed kinases (p-k) is a prerequisite for gsk3-dependent phosphorylation of thr-58. This triggers binding of pin1, subsequently protein phosphatase 2a (pp2a)-dependent dephosphorylation of ser-62, and then recruitment of scf-fbw7 to the thr-58-phosphorylated myc. Scf-fbw7 polyubiquitinylates myc (branching through lys-48), leading to its proteasomal degradation.	SIGNOR-149726
Q13489	Q99558	1	ubiquitination	down-regulates	0.65	Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation.	SIGNOR-167298
P00747	P25116	1	cleavage	down-regulates activity	0.624	Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site.	SIGNOR-263572
P01106	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.72	Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc.	SIGNOR-252080
Q9Y4K3	P49321	2	binding	down-regulates activity	0.2	SNASP inhibits TLR4-induced NF-κB activation through TRAF6.Reciprocal immunoprecipitation and Western blot analyses confirmed that endogenous sNASP binds to TRAF6 in human monocyte cell line THP-1 (Figure 1B).Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.	SIGNOR-273655
P12931	P23470	0	dephosphorylation	down-regulates activity	0.307	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254725
Q7Z3C6	P12931	0	phosphorylation	up-regulates activity	0.342	Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation.	SIGNOR-266367
P98082	Q5VWQ8	2	binding	up-regulates activity	0.521	In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.	SIGNOR-254744
P17612	P33076	1	phosphorylation	down-regulates activity	0.309	Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription.	SIGNOR-108569
P20339	Q99570	2	binding	up-regulates activity	0.422	Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15\|Rab5GTP binds Vps15, enhancing Vps34 activity	SIGNOR-260708
Q01105	P15531	2	binding	down-regulates	0.728	Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set.	SIGNOR-99205
P41002	P68400	0	phosphorylation	down-regulates activity	0.249	We determined that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF(cyclin F) complex.	SIGNOR-266373
P63000	Q96BY6	0	guanine nucleotide exchange factor	up-regulates activity	0.522	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-260549
P68431	Q9UQB9	0	phosphorylation	up-regulates activity	0.2	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-118898
Q9Y618	P06401	1	acetylation	down-regulates	0.588	In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.	SIGNOR-101289
P62714	Q9BXL7	1	dephosphorylation	down-regulates activity	0.2	NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane\|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.	SIGNOR-248607
Q9UKB1	P84022	1	ubiquitination	up-regulates	0.261	Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.	SIGNOR-108240
P09467	P37275	0	transcriptional regulation	down-regulates quantity by repression	0.2	Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells\|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells.	SIGNOR-267596
Q9NP60	P62166	2	binding	up-regulates activity	0.321	IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.	SIGNOR-264476
O43474	P35222	2	binding	up-regulates activity	0.686	The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.	SIGNOR-242100
Q8IUQ4	P04637	0	transcriptional regulation	up-regulates quantity by expression	0.372	P53 directly induces the expression of Siah-1 and in turn formation of a unique SCF-like complex (SCF(TBL1)) comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin β-like 1 (TBL1), and APC	SIGNOR-271953
P55957	Q13315	0	phosphorylation	down-regulates activity	0.463	Taken together, these results are consistent with the idea that at low levels of DNA damage ATM phosphorylates Bid to keep it away from the mitochondria resulting in low levels of ROS.\|Thus, Bid accumulation at the mitochondria, which is negatively regulated by ATM, triggers a metabolic change in mitochondria that includes an increase in ROS and perhaps changes in other metabolites that signal back to the nucleus to regulate gene transcription leading to cell cycle progression (XREF_FIG).	SIGNOR-279790
P26012	Q9Y490	2	binding	up-regulates activity	0.469	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257636
P46531	Q8NFP9	2	binding	down-regulates activity	0.305	Yeast two-hybrid identified the Notch1 intracellular domain as a physical interactor of the PBW domain and a role for NBEA as a negative regulator in Notch-mediated transcription was demonstrated.\|Defining novel interaction partners of conserved NBEA domain modules identified a role for NBEA as transcriptional regulator in the nucleus. The physical interaction of NBEA with NOTCH1 is most relevant for ASD pathogenesis because NOTCH signaling is essential for neural development.	SIGNOR-266010
Q9UK32	Q9UK32	2	phosphorylation	up-regulates activity	0.2	These mutants had minimal kinase activity and showed profoundly decreased phosphorylation at Ser232 compared with wild-type RSK4 (Fig 10B), suggesting that RSK4 can autophosphorylate at Ser232.	SIGNOR-275797
P09486	P15036	0	transcriptional regulation	up-regulates quantity by expression	0.305	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259874
P01116	P49354	0	null	up-regulates activity	0.382	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242559
P06493	P78549	1	phosphorylation	up-regulates activity	0.33	The main cell cycle kinase Cdk1 directly phosphorylates and activates the trehalase Nth1 to trigger the flux of storage carbohydrates into central carbon metabolism.	SIGNOR-278916
Q9NR31	O95487	2	binding	up-regulates quantity	0.746	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.	SIGNOR-265300
P04049	Q9BRX9	2	binding	up-regulates	0.525	Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.	SIGNOR-124476
Q9UHB9	P09132	2	binding	up-regulates activity	0.95	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.	SIGNOR-261167
O43781	P18848	0	transcriptional regulation	down-regulates quantity by repression	0.2	Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop.	SIGNOR-275453
O75385	Q9Y4P1	1	phosphorylation	down-regulates activity	0.614	Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316.\|Thus ULK1 is able to inhibit LC3 processing by a direct effect on ATG4B, possibly by phosphorylation of a serine residue of ATG4B.Fig. 1ULK1 inhibits ATG4B-mediated LC3 cleavage. a Average ATG4B activity in Actin-LC3-DelN Luciferase HEK293T obtained by measuring the secreted luciferase activity 48 h after transfection with the indicated constructs (n = 3, average \u00b1 s.d.) and representative immunoblot from one experiment showing expression of the different constructs. b GST-LC3 assay to measure in vitro activity of recombinant ATG4B after incubation with active recombinant ULK1.	SIGNOR-279434
Q99558	Q9Y4K3	2	binding	up-regulates activity	0.631	RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK.	SIGNOR-253048
Q99933	Q8NI51	0	transcriptional regulation	up-regulates quantity by expression	0.28	DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation	SIGNOR-254107
P59595	P55212	0	cleavage	up-regulates activity	0.2	Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403	SIGNOR-260212
P11532	Q01484	0	relocalization	up-regulates quantity	0.53	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266712
P06493	Q8ND76	1	phosphorylation	down-regulates activity	0.595	Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.\|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division.	SIGNOR-279012
Q13393	P54646	0	phosphorylation	up-regulates	0.2	Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp.	SIGNOR-164293
Q09472	Q6DJT9	1	acetylation	up-regulates	0.308	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140915
P28702	P10276	2	binding	up-regulates	0.722	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16674
Q9UBK2	Q16539	0	phosphorylation	up-regulates	0.586	Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298	SIGNOR-112774
Q07812	P55957	2	binding	up-regulates	0.825	Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax.	SIGNOR-73902
Q14765	P52564	0	phosphorylation	up-regulates activity	0.342	MKK6, phosphorylate STAT4 on serine 721. IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity.	SIGNOR-251425
P12931	Q9NZQ3	1	phosphorylation	up-regulates activity	0.414	These results indicate that phosphorylation of SPIN90 by Src is essential for its synaptic targeting.	SIGNOR-279387
Q12913	P12931	2	phosphorylation	up-regulates activity	0.636	CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation.	SIGNOR-277877
P68400	P06493	2	phosphorylation	up-regulates	0.355	Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment.	SIGNOR-134846
P50148	P11229	2	binding	up-regulates activity	0.461	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-257014
P62805	Q8TDB6	0	monoubiquitination	down-regulates activity	0.2	Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage.	SIGNOR-271897
P42127	P33032	2	binding	down-regulates activity	0.5	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268713
Q92918	P62993	2	binding	up-regulates	0.453	The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2.	SIGNOR-63994
P06493	Q15149	1	phosphorylation	down-regulates	0.388	Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.	SIGNOR-41319
P27361	Q9HBH9	1	phosphorylation	up-regulates	0.517	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.	SIGNOR-48355
P31995	P06241	0	phosphorylation	up-regulates activity	0.2	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262677
Q15154	Q9BV73	1	relocalization	up-regulates	0.551	Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1	SIGNOR-133334
P61586	Q9NRY4	0	gtpase-activating protein	down-regulates activity	0.893	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-260492
Q03112	P24941	0	phosphorylation	up-regulates activity	0.296	The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.	SIGNOR-273426
O96013	Q92974	1	phosphorylation	down-regulates activity	0.518	PAK4 specifically phosphorylates GefH1, and this is thought to inhibit its ability to activate Rho, consequently inhibiting stress fiber formation.	SIGNOR-279245

P09471

P30542

2

binding

up-regulates activity

0.39

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-256976

Q12772

Q14703

0

cleavage

up-regulates activity

0.594

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

SIGNOR-267496

O95714

P38398

1

ubiquitination

down-regulates quantity by destabilization

0.561

HERC2 ubiquitinates BRCA1; this reaction depends on Cys(4762) of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1.|Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G(2)-M checkpoint activity.

SIGNOR-278813

P46531

Q9NWT6

0

hydroxylation

down-regulates

0.55

We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation.

SIGNOR-161057

P23769

P10828

2

binding

down-regulates activity

0.2

We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2.

SIGNOR-267256

P07196

P17612

0

phosphorylation

down-regulates activity

0.2

Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L.

SIGNOR-252401

P01266

Q06710

0

transcriptional regulation

up-regulates quantity by expression

0.458

The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression.

SIGNOR-251998

Q13683

P15173

0

transcriptional regulation

up-regulates quantity by expression

0.283

Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.

SIGNOR-241521

P43405

Q13191

0

ubiquitination

down-regulates quantity

0.696

In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.

SIGNOR-278754

Q96PN8

O15530

0

phosphorylation

up-regulates activity

0.261

We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.

SIGNOR-260786

P05019

P42229

0

transcriptional regulation

up-regulates quantity by expression

0.433

Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α

SIGNOR-251743

Q99759

P53805

1

phosphorylation

up-regulates

0.448

Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation

SIGNOR-102294

P49841

Q14449

1

phosphorylation

down-regulates activity

0.323

Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.

SIGNOR-264867

P49137

P04792

1

phosphorylation

down-regulates

0.809

Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.

SIGNOR-94021

Q9NP62

Q9P0U3

0

desumoylation

up-regulates activity

0.468

We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.

SIGNOR-262681

Q92630

P46531

1

phosphorylation

down-regulates quantity by destabilization

0.288

We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism.

SIGNOR-279035

P48730

O43312

1

phosphorylation

down-regulates quantity by destabilization

0.327

Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.

SIGNOR-276611

P06493

P23769

1

phosphorylation

down-regulates quantity by destabilization

0.355

GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1).

SIGNOR-276884

Q9H2X6

Q92793

1

phosphorylation

up-regulates activity

0.424

Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CREB-binding protein.|We show that HIPK2 interacts with and phosphorylates several regions of CBP.

SIGNOR-279191

Q05655

O00429

1

phosphorylation

up-regulates

0.2

Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation.

SIGNOR-153148

Q14185

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.735

We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.

SIGNOR-266822

Q92914

Q99250

2

binding

down-regulates activity

0.252

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253430

P12644

Q13253

2

binding

down-regulates

0.814

Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides

SIGNOR-100660

Q08999

P67775

0

dephosphorylation

up-regulates

0.581

Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation.

SIGNOR-129752

P57078

Q13489

0

polyubiquitination

up-regulates activity

0.355

CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.

SIGNOR-272709

P06493

Q9UPT9

1

phosphorylation

up-regulates activity

0.47

On the other hand, CDK1 enhances USP22 activity to stabilize CCNB1 during the G2/M phase.|Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1.

SIGNOR-278241

O60502

P11413

1

deglycosylation

down-regulates activity

0.2

O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.

SIGNOR-267605

Q9UQB3

P12830

2

binding

up-regulates quantity by stabilization

0.447

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252134

P38484

P01579

2

binding

up-regulates

0.649

Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction

SIGNOR-31013

Q969H0

Q8WUJ0

2

binding

down-regulates activity

0.346

STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients,

SIGNOR-251663

Q14493

P62807

1

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265377

O43602

P49841

0

phosphorylation

up-regulates activity

0.271

Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact.

SIGNOR-170755

P23470

P24941

1

dephosphorylation

down-regulates activity

0.298

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254695

P08151

P08631

0

phosphorylation

up-regulates activity

0.299

These results suggest that the interaction between Gli1 and Hck or the phosphorylation of Gli1 by Hck disrupts Sufu-Gli1 interaction.|We showed that tyrosine kinase Hck activates Gli1 and the kinase activity is required for its maximum effect.

SIGNOR-279374

Q13164

Q14814

1

phosphorylation

up-regulates

0.705

Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b. the sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.

SIGNOR-236041

P46108

P52564

0

phosphorylation

up-regulates

0.2

Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily.

SIGNOR-42384

Q9Y243

P04792

1

phosphorylation

down-regulates

0.286

First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.

SIGNOR-186780

P48050

P17252

0

phosphorylation

down-regulates activity

0.2

These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3.

SIGNOR-275965

O43592

P62826

2

binding

up-regulates activity

0.815

The first step in export appears to be the formation of a trimeric tRNA/exportin-t/RanGTP complex. tRNA and RanGTP bind to exportin-t in a highly cooperative manner: tRNA increases the affinity of exportin-t for RanGTP apparently 300-fold (Figure 5A); conversely, RanGTP has to increase the affinity of exportin-t for tRNA by the same factor. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus

SIGNOR-261392

P51812

P19634

1

phosphorylation

up-regulates activity

0.414

In pressured arteries, RSK2 dependent activation of NHE-1 was associated with increased intracellular Ca 2+ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses.|Together, these data indicate that Ser 703 in NHE-1 is phosphorylated by RSK2, that RSK2 is associated with NHE-1, and that the time course of NHE-1 phosphorylation in response to intraluminal pressure is fast enough for this phosphorylation event to contribute to myogenic vasoconstriction.

SIGNOR-280119

P62136

P46937

1

dephosphorylation

up-regulates activity

0.668

In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.|PP1A dephosphorylates endogenous YAP2 at serine 127.

SIGNOR-276999

Q9H0H5

P53350

0

phosphorylation

up-regulates

0.638

Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.

SIGNOR-185758

P01106

P62714

0

dephosphorylation

down-regulates

0.276

Phosphorylation at ser-62 by pro-directed kinases (p-k) is a prerequisite for gsk3-dependent phosphorylation of thr-58. This triggers binding of pin1, subsequently protein phosphatase 2a (pp2a)-dependent dephosphorylation of ser-62, and then recruitment of scf-fbw7 to the thr-58-phosphorylated myc. Scf-fbw7 polyubiquitinylates myc (branching through lys-48), leading to its proteasomal degradation.

SIGNOR-149726

Q13489

Q99558

1

ubiquitination

down-regulates

0.65

Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation.

SIGNOR-167298

P00747

P25116

1

cleavage

down-regulates activity

0.624

Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site.

SIGNOR-263572

P01106

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.72

Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc.

SIGNOR-252080

Q9Y4K3

P49321

2

binding

down-regulates activity

0.2

SNASP inhibits TLR4-induced NF-κB activation through TRAF6.Reciprocal immunoprecipitation and Western blot analyses confirmed that endogenous sNASP binds to TRAF6 in human monocyte cell line THP-1 (Figure 1B).Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.

SIGNOR-273655

P12931

P23470

0

dephosphorylation

down-regulates activity

0.307

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254725

Q7Z3C6

P12931

0

phosphorylation

up-regulates activity

0.342

Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation.

SIGNOR-266367

P98082

Q5VWQ8

2

binding

up-regulates activity

0.521

In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.

SIGNOR-254744

P17612

P33076

1

phosphorylation

down-regulates activity

0.309

Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription.

SIGNOR-108569

P20339

Q99570

2

binding

up-regulates activity

0.422

Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity

SIGNOR-260708

Q01105

P15531

2

binding

down-regulates

0.728

Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set.

SIGNOR-99205

P41002

P68400

0

phosphorylation

down-regulates activity

0.249

We determined that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF(cyclin F) complex.

SIGNOR-266373

P63000

Q96BY6

0

guanine nucleotide exchange factor

up-regulates activity

0.522

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-260549

P68431

Q9UQB9

0

phosphorylation

up-regulates activity

0.2

Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.

SIGNOR-118898

Q9Y618

P06401

1

acetylation

down-regulates

0.588

In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.

SIGNOR-101289

P62714

Q9BXL7

1

dephosphorylation

down-regulates activity

0.2

NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.

SIGNOR-248607

Q9UKB1

P84022

1

ubiquitination

up-regulates

0.261

Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.

SIGNOR-108240

P09467

P37275

0

transcriptional regulation

down-regulates quantity by repression

0.2

Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells.

SIGNOR-267596

Q9NP60

P62166

2

binding

up-regulates activity

0.321

IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.

SIGNOR-264476

O43474

P35222

2

binding

up-regulates activity

0.686

The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.

SIGNOR-242100

Q8IUQ4

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.372

P53 directly induces the expression of Siah-1 and in turn formation of a unique SCF-like complex (SCF(TBL1)) comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin β-like 1 (TBL1), and APC

SIGNOR-271953

P55957

Q13315

0

phosphorylation

down-regulates activity

0.463

Taken together, these results are consistent with the idea that at low levels of DNA damage ATM phosphorylates Bid to keep it away from the mitochondria resulting in low levels of ROS.|Thus, Bid accumulation at the mitochondria, which is negatively regulated by ATM, triggers a metabolic change in mitochondria that includes an increase in ROS and perhaps changes in other metabolites that signal back to the nucleus to regulate gene transcription leading to cell cycle progression (XREF_FIG).

SIGNOR-279790

P26012

Q9Y490

2

binding

up-regulates activity

0.469

Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.

SIGNOR-257636

P46531

Q8NFP9

2

binding

down-regulates activity

0.305

Yeast two-hybrid identified the Notch1 intracellular domain as a physical interactor of the PBW domain and a role for NBEA as a negative regulator in Notch-mediated transcription was demonstrated.|Defining novel interaction partners of conserved NBEA domain modules identified a role for NBEA as transcriptional regulator in the nucleus. The physical interaction of NBEA with NOTCH1 is most relevant for ASD pathogenesis because NOTCH signaling is essential for neural development.

SIGNOR-266010

Q9UK32

2

phosphorylation

up-regulates activity

0.2

These mutants had minimal kinase activity and showed profoundly decreased phosphorylation at Ser232 compared with wild-type RSK4 (Fig 10B), suggesting that RSK4 can autophosphorylate at Ser232.

SIGNOR-275797

P09486

P15036

0

transcriptional regulation

up-regulates quantity by expression

0.305

Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin

SIGNOR-259874

P01116

P49354

0

null

up-regulates activity

0.382

Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.

SIGNOR-242559

P06493

P78549

1

phosphorylation

up-regulates activity

0.33

The main cell cycle kinase Cdk1 directly phosphorylates and activates the trehalase Nth1 to trigger the flux of storage carbohydrates into central carbon metabolism.

SIGNOR-278916

Q9NR31

O95487

2

binding

up-regulates quantity

0.746

Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.

SIGNOR-265300

P04049

Q9BRX9

2

binding

up-regulates

0.525

Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.

SIGNOR-124476

Q9UHB9

P09132

2

binding

up-regulates activity

0.95

Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.

SIGNOR-261167

O43781

P18848

0

transcriptional regulation

down-regulates quantity by repression

0.2

Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop.

SIGNOR-275453

O75385

Q9Y4P1

1

phosphorylation

down-regulates activity

0.614

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

SIGNOR-279434

Q99558

Q9Y4K3

2

binding

up-regulates activity

0.631

RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK.

SIGNOR-253048

Q99933

Q8NI51

0

transcriptional regulation

up-regulates quantity by expression

0.28

DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation

SIGNOR-254107

P59595

P55212

0

cleavage

up-regulates activity

0.2

Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403

SIGNOR-260212

P11532

Q01484

0

relocalization

up-regulates quantity

0.53

We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.

SIGNOR-266712

P06493

Q8ND76

1

phosphorylation

down-regulates activity

0.595

Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division.

SIGNOR-279012

Q13393

P54646

0

phosphorylation

up-regulates

0.2

Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp.

SIGNOR-164293

Q09472

Q6DJT9

1

acetylation

up-regulates

0.308

Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.

SIGNOR-140915

P28702

P10276

2

binding

up-regulates

0.722

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16674

Q9UBK2

Q16539

0

phosphorylation

up-regulates

0.586

Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298

SIGNOR-112774

Q07812

P55957

2

binding

up-regulates

0.825

Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax.

SIGNOR-73902

Q14765

P52564

0

phosphorylation

up-regulates activity

0.342

MKK6, phosphorylate STAT4 on serine 721. IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity.

SIGNOR-251425

P12931

Q9NZQ3

1

phosphorylation

up-regulates activity

0.414

These results indicate that phosphorylation of SPIN90 by Src is essential for its synaptic targeting.

SIGNOR-279387

Q12913

P12931

2

phosphorylation

up-regulates activity

0.636

CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation.

SIGNOR-277877

P68400

P06493

2

phosphorylation

up-regulates

0.355

Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment.

SIGNOR-134846

P50148

P11229

2

binding

up-regulates activity

0.461

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-257014

P62805

Q8TDB6

0

monoubiquitination

down-regulates activity

0.2

Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage.

SIGNOR-271897

P42127

P33032

2

binding

down-regulates activity

0.5

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

SIGNOR-268713

Q92918

P62993

2

binding

up-regulates

0.453

The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2.

SIGNOR-63994

P06493

Q15149

1

phosphorylation

down-regulates

0.388

Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.

SIGNOR-41319

P27361

Q9HBH9

1

phosphorylation

up-regulates

0.517

Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.

SIGNOR-48355

P31995

P06241

0

phosphorylation

up-regulates activity

0.2

Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation

SIGNOR-262677

Q15154

Q9BV73

1

relocalization

up-regulates

0.551

Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1

SIGNOR-133334

P61586

Q9NRY4

0

gtpase-activating protein

down-regulates activity

0.893

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-260492

Q03112

P24941

0

phosphorylation

up-regulates activity

0.296

The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.

SIGNOR-273426

O96013

Q92974

1

phosphorylation

down-regulates activity

0.518

PAK4 specifically phosphorylates GefH1, and this is thought to inhibit its ability to activate Rho, consequently inhibiting stress fiber formation.

SIGNOR-279245