GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q9H9Q4	P31749	phosphorylation	down-regulates quantity by destabilization	0.358	Akt1 phosphorylates XLF at T181 Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3β leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(β-TRCP) in a CKI-dependent manner.	SIGNOR-276881
Q03113	P21554	binding	up-regulates activity	0.358	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-257285
O14640	Q9GZV5	binding	down-regulates	0.358	Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation.	SIGNOR-195212
Q12778	Q13153	phosphorylation	down-regulates activity	0.358	Pak1 efficiently phosphorylated GST-FKHR.	SIGNOR-279242
Q9NQB0	P68400	phosphorylation	up-regulates activity	0.358	We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. \| Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4.	SIGNOR-250963
O00327	P31751	phosphorylation	down-regulates activity	0.358	Consistent with mass spectrometry results, constitutive active Akt2 (Akt2-CA) induced wild-type (WT) Bmal1 protein phosphorylation, which was abolished by a serine to alanine mutation at Ser42 residue (S42A) but not a S422A/S513A double mutation, as shown by immunoblot assay with phospho-Akt substrate antiserum ( xref ).\|In line with the in vivo results, overexpression of Akt2-CA strikingly lowered Bmal1 protein abundance in the nucleus in primary hepatocytes (XREF_FIG and XREF_SUPPLEMENTARY).	SIGNOR-280177
P35568	Q15418	phosphorylation	down-regulates quantity by destabilization	0.358	Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization.	SIGNOR-175687
O75365	P12931	phosphorylation	down-regulates activity	0.358	Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.\|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification.	SIGNOR-278262
Q12772	P28482	phosphorylation	up-regulates	0.358	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-123045
P56524	Q13557	phosphorylation	up-regulates	0.358	These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2	SIGNOR-151418
P26358	Q00535	phosphorylation	up-regulates	0.358	We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5	SIGNOR-173685
Q9UQ26	Q9UFD9	binding	down-regulates activity	0.358	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264365
P09874	P24941	phosphorylation	up-regulates activity	0.358	CDK2 dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells.\|Hormone dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities.	SIGNOR-279146
O14795	Q9UQ26	relocalization	up-regulates activity	0.358	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264383
O95071	P23193	binding	up-regulates	0.358	We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination.	SIGNOR-170258
P10071	Q15915	relocalization	up-regulates	0.358	Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels	SIGNOR-105497
O75581	Q6IMN6	binding	up-regulates	0.358	A cytoplasmic protein in vertebrates, referred to as caprin-2, binds to lrp6 and facilitates lrp6 phosphorylation by gsk3	SIGNOR-187177
Q13569	Q9NZJ0	binding	down-regulates quantity by destabilization	0.358	TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner	SIGNOR-272847
P01574	O15226	transcriptional regulation	down-regulates quantity by repression	0.358	Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB	SIGNOR-266227
Q9Y6K9	P06241	phosphorylation	down-regulates activity	0.357	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.	SIGNOR-276371
P04843	Q8WXH4	polyubiquitination	down-regulates quantity by destabilization	0.357	We also demonstrated that ASB11 is a novel endoplasmic reticulum-associated ubiquitin ligase with the ability to interact and promote the ubiquitination of Ribophorin 1, an integral protein of the oligosaccharyltransferase (OST) glycosylation complex. Moreover, expression of ASB11 can increase Ribophorin 1 protein turnover in vivo.	SIGNOR-272057
P09874	Q13535	phosphorylation	down-regulates	0.357	Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments.\|These data suggest that the phosphorylation of S179 is necessary and sufficient for ATR inhibition of PARP1 PARylation activity.	SIGNOR-278506
P17844	P00519	phosphorylation	up-regulates	0.357	These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway.	SIGNOR-149988
Q13153	P67775	dephosphorylation	down-regulates activity	0.357	Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248641
Q05682	P17252	phosphorylation	down-regulates	0.357	Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase.	SIGNOR-36792
P29475	Q16566	phosphorylation	down-regulates activity	0.357	It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.	SIGNOR-250713
P39880	P06493	phosphorylation	down-regulates	0.357	Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter.	SIGNOR-110912
P42224	Q07912	phosphorylation	up-regulates activity	0.357	Hence, ACK1 activates STAT1 through its kinase activity.\|We found that wild-type ACK1 and to a larger extent constitutively active ACK1 increased the phosphorylation of cytoplasmic STAT1 at Y701.	SIGNOR-278348
P17542	P27361	phosphorylation	down-regulates	0.357	We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of tal1 in endothelial cells. A specific serine in the putative transactivation domain of the protein, ser122, is preferentially phosphorylated by mapk in vitro.	SIGNOR-116153
P63092	P41594	binding	up-regulates activity	0.357	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264078
Q04206	P49841	phosphorylation	up-regulates	0.357	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .	SIGNOR-151422
Q8NEB9	Q00535	phosphorylation	down-regulates	0.357	Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34.	SIGNOR-165772
Q16531	Q9NRC8	deacetylation	down-regulates activity	0.357	Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction.	SIGNOR-275900
P03372	O14965	phosphorylation	up-regulates activity	0.357	Based on these findings, we conclude that ER\u03b1-Ser167 and -Ser305 are phosphorylated by Aurora-A in vitro and in vivo .\|These data suggest that Aurora-A not only activates ER\u03b1 activity but also enhances E2 action and that Aurora-A-induced ER\u03b1 activation could not be inhibited by tamoxifen.	SIGNOR-278508
Q12929	Q13882	phosphorylation	up-regulates activity	0.357	Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis.	SIGNOR-263191
P63092	Q14831	binding	up-regulates activity	0.357	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264080
Q12888	P60510	dephosphorylation	up-regulates activity	0.357	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.\|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks \|Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618	SIGNOR-264450
O95863	P0C2W1	binding	down-regulates quantity by destabilization	0.357	One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.	SIGNOR-272181
P19429	Q13976	phosphorylation	up-regulates activity	0.357	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134644
P07910	P68400	phosphorylation	down-regulates activity	0.357	In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.	SIGNOR-133540
Q15858	Q92913	binding	down-regulates activity	0.357	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-253423
P11362	P51812	phosphorylation	down-regulates quantity	0.357	Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity.	SIGNOR-276599
P00533	P51452	dephosphorylation	down-regulates activity	0.357	We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR.	SIGNOR-248532
P26651	Q16539	phosphorylation	down-regulates activity	0.357	TTP appears to be a p38Î±/Î² MAPK target and pretreating skeletal muscle with a p38Î±/Î² MAPK inhibitor reduces TTP phosphorylation.	SIGNOR-253596
P46108	Q18PE1	binding	up-regulates activity	0.357	Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7.	SIGNOR-273847
Q9Y4G8	Q9NYY3	phosphorylation	up-regulates activity	0.357	Here, we report that Plk2 phosphorylates a quartet of Ras and Rap regulators : SynGAP, PDZGEF1, RasGRF1 and SPAR, resulting in powerful bidirectional control over Rap and Ras activity.\|Thus, Plk2 was sufficient to promote the activities of both SynGAP and PDZGEF1 in mammalian cells.	SIGNOR-280066
Q13642	Q06587	binding	up-regulates	0.357	The polycombprotein ring1 interacts with the lim domains of kyot2 in yeast and mammalian cells. The interaction between kyot2 and ring1 was detected both in vitro and in vivo	SIGNOR-123150
Q07955	Q9HAZ1	phosphorylation	up-regulates activity	0.357	In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.	SIGNOR-273860
P49841	P17252	phosphorylation	down-regulates	0.357	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188581
Q16623	Q86UW7	binding	up-regulates activity	0.357	CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1	SIGNOR-264337
Q13309	O60729	dephosphorylation	down-regulates quantity by destabilization	0.357	The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).	SIGNOR-248333
P52292	Q09472	acetylation	up-regulates	0.357	Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300	SIGNOR-128625
Q13153	O15530	phosphorylation	up-regulates activity	0.357	P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1.	SIGNOR-250267
Q9Y6K9	P07948	phosphorylation	down-regulates activity	0.357	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.	SIGNOR-276369
Q14247	Q9P2B4	binding	up-regulates activity	0.357	CTTNBP2NL interacts with cortactin and targets cortactin to stress fibers.	SIGNOR-261695
Q5JVL4	Q92949	transcriptional regulation	up-regulates quantity by expression	0.356	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266934
Q8N165	Q05D32	dephosphorylation	up-regulates quantity by stabilization	0.356	We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D).	SIGNOR-273773
P22626	P01106	transcriptional regulation	up-regulates quantity by expression	0.356	We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,	SIGNOR-268691
Q8N6F7	P43405	phosphorylation	up-regulates activity	0.356	Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation.	SIGNOR-273570
Q96P20	Q9Y2R2	dephosphorylation	up-regulates activity	0.356	Further, this explains how loss of PTPN22 and subsequent enhanced NLRP3 phosphorylation mediate a decrease in NLRP3 inflammasome activation.\|Upon NLRP3 activation, PTPN22 dephosphorylates NLRP3 and thereby protects it from degradation, allowing robust inflammasome activity (summarized in Fig.S6).	SIGNOR-277056
Q00987	P62136	dephosphorylation	up-regulates quantity by stabilization	0.356	Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.	SIGNOR-248566
Q13188	P31749	phosphorylation	down-regulates	0.356	We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.	SIGNOR-163533
O75628	Q15139	phosphorylation	up-regulates activity	0.356	We found that activation of protein kinase D1, a protein kinase downstream of α(1)-adrenergic signaling, leads to direct phosphorylation of Rem1 at Ser18. This results in an increase of the channel activity and plasma membrane expression observed by using a combination of electrophysiology, live cell confocal microscopy, and immunohistochemistry in heterologous expression system and neonatal cardiomyocytes.	SIGNOR-273832
Q12778	Q13237	phosphorylation	up-regulates activity	0.356	Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2.	SIGNOR-279564
P17542	Q9UNE7	ubiquitination	down-regulates quantity by destabilization	0.356	Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively.	SIGNOR-271393
Q01130	Q9UBN7	deacetylation	up-regulates	0.356	Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation.	SIGNOR-170590
Q9Y4X5	Q13616	binding	up-regulates activity	0.356	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268844
O14640	P31431	binding	up-regulates	0.356	Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1.	SIGNOR-199632
P43694	P11802	phosphorylation	up-regulates activity	0.356	In addition, we have shown that CDK4 can enhance cardiogenic activity of GATA4 (XREF_FIG).\|The physical and functional interactions between GATA4 and Cyclin D2 depend on phosphorylation of Ser 160 of GATA4, which can be mediated in vitro by CDK4.	SIGNOR-279148
P08151	O14920	phosphorylation	up-regulates activity	0.356	Active IKKbeta promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma.\|Herein, we demonstrate that IKKbeta phosphorylates GLI1 in DLBCL.	SIGNOR-279194
P08047	Q01664	binding	up-regulates activity	0.356	We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.	SIGNOR-226593
P17480	P01106	transcriptional regulation	up-regulates quantity by expression	0.356	MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation\|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.	SIGNOR-269644
Q13794	Q00535	phosphorylation	down-regulates	0.356	We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase	SIGNOR-170357
O95238	Q9UQ88	phosphorylation	down-regulates quantity by destabilization	0.356	In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues\|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.\|	SIGNOR-273022
Q8IV63	Q00535	phosphorylation	up-regulates activity	0.356	Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding\|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation\|	SIGNOR-275544
O15519	Q9UNE7	ubiquitination	down-regulates quantity by destabilization	0.356	Taken together, our data suggest that CHIP interacts with c-FLIP L in vivo and promotes the ubiquitination of c-FLIP L.\|When we knocked down CHIP, c-FLIP L degradation was inhibited after treatment with 17-AAG, which indicated that CHIP modulated c-FLIP L degradation in the NSCLC cell lines.	SIGNOR-278783
P52948	Q08211	binding	up-regulates activity	0.356	Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription.	SIGNOR-260954
O15055	Q00987	polyubiquitination	down-regulates quantity by destabilization	0.356	We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation.	SIGNOR-277421
Q92519	P23443	phosphorylation	down-regulates quantity by destabilization	0.356	Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2.	SIGNOR-275433
P09471	P21918	binding	up-regulates activity	0.356	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-257244
Q9UQL6	P34947	phosphorylation	down-regulates activity	0.356	GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5.	SIGNOR-279045
P49815	O75592	ubiquitination	down-regulates quantity by destabilization	0.356	We show that Pam associates with E2 ubiquitin conjugating enzymes, and tuberin can be ubiquitinated by Pam through its RING finger domain.	SIGNOR-278704
O95251	P06493	phosphorylation	up-regulates	0.355	Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.	SIGNOR-160747
P57078	Q13490	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-272708
P57078	Q13489	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
P29317	P31749	phosphorylation	up-regulates activity	0.355	As non-canonical EphA2 activation requires phosphorylation of EphA2 at serine 897 by pAkt (Fig.\u00a02b), we sought to determine the effect of PTEN-mediated Akt regulation on invasion.	SIGNOR-279787
P29590	Q6ZNA4	polyubiquitination	down-regulates quantity by destabilization	0.355	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-272883
Q14721	P23469	dephosphorylation	down-regulates activity	0.355	Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon	SIGNOR-248450
O94761	P06493	phosphorylation	up-regulates activity	0.355	During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.	SIGNOR-277375
P51812	P12931	phosphorylation	up-regulates	0.355	Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway.	SIGNOR-160052
Q9BST9	Q15139	phosphorylation	up-regulates activity	0.355	Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane.	SIGNOR-275511
Q13444	P08631	phosphorylation	up-regulates	0.355	Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.	SIGNOR-112919
P06239	P04150	binding	up-regulates	0.355	The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation.	SIGNOR-251685
Q15139	P24723	phosphorylation	up-regulates	0.355	These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.	SIGNOR-66734
Q03113	Q9H1C0	binding	up-regulates activity	0.355	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-257205
P78362	P23443	phosphorylation	up-regulates activity	0.355	Altogether, these results identify S6K1-phosphorylated SRPK2 as an essential mediator of IGF1-stimulated SG formation in hPDAC cells.\|The nodes of the core SG network are known to contribute to SG formation to varying degrees and it is possible that S6K1-stimulated SRPK2 may impact their contribution; this is consistent with the predicted model whereby SG assembly is subject to regulation by positive and negative cooperativity of extrinsic factors with the core network interactions (14).	SIGNOR-280121
Q9BX46	Q15208	phosphorylation	up-regulates activity	0.355	Phosphorylation of Rbm24 by Stk38 is crucial for the maintenance of cardiac sarcomeric gene expression in cardiac cells.\|These results indicated that Stk38 increases Rbm24 protein stability probably by interfering with the ubiquitin-proteasome protein degradation pathway.	SIGNOR-278291
Q9NY61	Q13315	phosphorylation	up-regulates quantity by stabilization	0.355	The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. \|DNA damage stabilizes Che-1 protein\|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site.	SIGNOR-264415
P12931	P45984	phosphorylation	up-regulates activity	0.355	Activation of c-Src by JNK2 was accompanied by the phosphorylation of c-Src on threonine residue (s).\|JNK2 directly phosphorylates c-Src and activates its auto phosphorylation.	SIGNOR-279221
P40925	Q86X55	acetylation	down-regulates activity	0.355	Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer\|Arginine methylation at R248 negatively regulates MDH1 activity\|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization	SIGNOR-267639

Q9H9Q4

P31749

0

phosphorylation

down-regulates quantity by destabilization

0.358

Akt1 phosphorylates XLF at T181 Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3β leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(β-TRCP) in a CKI-dependent manner.

SIGNOR-276881

Q03113

P21554

0

binding

up-regulates activity

0.358

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-257285

O14640

Q9GZV5

0

binding

down-regulates

0.358

Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation.

SIGNOR-195212

Q12778

Q13153

0

phosphorylation

down-regulates activity

0.358

Pak1 efficiently phosphorylated GST-FKHR.

SIGNOR-279242

Q9NQB0

P68400

0

phosphorylation

up-regulates activity

0.358

We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4.

SIGNOR-250963

O00327

P31751

0

phosphorylation

down-regulates activity

0.358

Consistent with mass spectrometry results, constitutive active Akt2 (Akt2-CA) induced wild-type (WT) Bmal1 protein phosphorylation, which was abolished by a serine to alanine mutation at Ser42 residue (S42A) but not a S422A/S513A double mutation, as shown by immunoblot assay with phospho-Akt substrate antiserum ( xref ).|In line with the in vivo results, overexpression of Akt2-CA strikingly lowered Bmal1 protein abundance in the nucleus in primary hepatocytes (XREF_FIG and XREF_SUPPLEMENTARY).

SIGNOR-280177

P35568

Q15418

0

phosphorylation

down-regulates quantity by destabilization

0.358

Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization.

SIGNOR-175687

O75365

P12931

0

phosphorylation

down-regulates activity

0.358

Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification.

SIGNOR-278262

Q12772

P28482

0

phosphorylation

up-regulates

0.358

Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.

SIGNOR-123045

P56524

Q13557

0

phosphorylation

up-regulates

0.358

These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2

SIGNOR-151418

P26358

Q00535

0

phosphorylation

up-regulates

0.358

We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5

SIGNOR-173685

Q9UQ26

Q9UFD9

0

binding

down-regulates activity

0.358

SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.

SIGNOR-264365

P09874

P24941

0

phosphorylation

up-regulates activity

0.358

CDK2 dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells.|Hormone dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities.

SIGNOR-279146

O14795

Q9UQ26

0

relocalization

up-regulates activity

0.358

N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle

SIGNOR-264383

O95071

P23193

0

binding

up-regulates

0.358

We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination.

SIGNOR-170258

P10071

Q15915

0

relocalization

up-regulates

0.358

Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels

SIGNOR-105497

O75581

Q6IMN6

0

binding

up-regulates

0.358

A cytoplasmic protein in vertebrates, referred to as caprin-2, binds to lrp6 and facilitates lrp6 phosphorylation by gsk3

SIGNOR-187177

Q13569

Q9NZJ0

0

binding

down-regulates quantity by destabilization

0.358

TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner

SIGNOR-272847

P01574

O15226

0

transcriptional regulation

down-regulates quantity by repression

0.358

Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB

SIGNOR-266227

Q9Y6K9

P06241

0

phosphorylation

down-regulates activity

0.357

Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.

SIGNOR-276371

P04843

Q8WXH4

0

polyubiquitination

down-regulates quantity by destabilization

0.357

We also demonstrated that ASB11 is a novel endoplasmic reticulum-associated ubiquitin ligase with the ability to interact and promote the ubiquitination of Ribophorin 1, an integral protein of the oligosaccharyltransferase (OST) glycosylation complex. Moreover, expression of ASB11 can increase Ribophorin 1 protein turnover in vivo.

SIGNOR-272057

P09874

Q13535

0

phosphorylation

down-regulates

0.357

Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments.|These data suggest that the phosphorylation of S179 is necessary and sufficient for ATR inhibition of PARP1 PARylation activity.

SIGNOR-278506

P17844

P00519

0

phosphorylation

up-regulates

0.357

These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway.

SIGNOR-149988

Q13153

P67775

0

dephosphorylation

down-regulates activity

0.357

Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.

SIGNOR-248641

Q05682

P17252

0

phosphorylation

down-regulates

0.357

Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase.

SIGNOR-36792

P29475

Q16566

0

phosphorylation

down-regulates activity

0.357

It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.

SIGNOR-250713

P39880

P06493

0

phosphorylation

down-regulates

0.357

Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter.

SIGNOR-110912

P42224

Q07912

0

phosphorylation

up-regulates activity

0.357

Hence, ACK1 activates STAT1 through its kinase activity.|We found that wild-type ACK1 and to a larger extent constitutively active ACK1 increased the phosphorylation of cytoplasmic STAT1 at Y701.

SIGNOR-278348

P17542

P27361

0

phosphorylation

down-regulates

0.357

We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of tal1 in endothelial cells. A specific serine in the putative transactivation domain of the protein, ser122, is preferentially phosphorylated by mapk in vitro.

SIGNOR-116153

P63092

P41594

0

binding

up-regulates activity

0.357

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

SIGNOR-264078

Q04206

P49841

0

phosphorylation

up-regulates

0.357

Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .

SIGNOR-151422

Q8NEB9

Q00535

0

phosphorylation

down-regulates

0.357

Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34.

SIGNOR-165772

Q16531

Q9NRC8

0

deacetylation

down-regulates activity

0.357

Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction.

SIGNOR-275900

P03372

O14965

0

phosphorylation

up-regulates activity

0.357

Based on these findings, we conclude that ER\u03b1-Ser167 and -Ser305 are phosphorylated by Aurora-A in vitro and in vivo .|These data suggest that Aurora-A not only activates ER\u03b1 activity but also enhances E2 action and that Aurora-A-induced ER\u03b1 activation could not be inhibited by tamoxifen.

SIGNOR-278508

Q12929

Q13882

0

phosphorylation

up-regulates activity

0.357

Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis.

SIGNOR-263191

P63092

Q14831

0

binding

up-regulates activity

0.357

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

SIGNOR-264080

Q12888

P60510

0

dephosphorylation

up-regulates activity

0.357

Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618

SIGNOR-264450

O95863

P0C2W1

0

binding

down-regulates quantity by destabilization

0.357

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

SIGNOR-272181

P19429

Q13976

0

phosphorylation

up-regulates activity

0.357

Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.

SIGNOR-134644

P07910

P68400

0

phosphorylation

down-regulates activity

0.357

In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.

SIGNOR-133540

Q15858

Q92913

0

binding

down-regulates activity

0.357

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-253423

P11362

P51812

0

phosphorylation

down-regulates quantity

0.357

Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity.

SIGNOR-276599

P00533

P51452

0

dephosphorylation

down-regulates activity

0.357

We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR.

SIGNOR-248532

P26651

Q16539

0

phosphorylation

down-regulates activity

0.357

TTP appears to be a p38Î±/Î² MAPK target and pretreating skeletal muscle with a p38Î±/Î² MAPK inhibitor reduces TTP phosphorylation.

SIGNOR-253596

P46108

Q18PE1

0

binding

up-regulates activity

0.357

Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7.

SIGNOR-273847

Q9Y4G8

Q9NYY3

0

phosphorylation

up-regulates activity

0.357

Here, we report that Plk2 phosphorylates a quartet of Ras and Rap regulators : SynGAP, PDZGEF1, RasGRF1 and SPAR, resulting in powerful bidirectional control over Rap and Ras activity.|Thus, Plk2 was sufficient to promote the activities of both SynGAP and PDZGEF1 in mammalian cells.

SIGNOR-280066

Q13642

Q06587

0

binding

up-regulates

0.357

The polycombprotein ring1 interacts with the lim domains of kyot2 in yeast and mammalian cells. The interaction between kyot2 and ring1 was detected both in vitro and in vivo

SIGNOR-123150

Q07955

Q9HAZ1

0

phosphorylation

up-regulates activity

0.357

In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.

SIGNOR-273860

P49841

P17252

0

phosphorylation

down-regulates

0.357

Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).

SIGNOR-188581

Q16623

Q86UW7

0

binding

up-regulates activity

0.357

CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1

SIGNOR-264337

Q13309

O60729

0

dephosphorylation

down-regulates quantity by destabilization

0.357

The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).

SIGNOR-248333

P52292

Q09472

0

acetylation

up-regulates

0.357

Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300

SIGNOR-128625

Q13153

O15530

0

phosphorylation

up-regulates activity

0.357

P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1.

SIGNOR-250267

Q9Y6K9

P07948

0

phosphorylation

down-regulates activity

0.357

Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.

SIGNOR-276369

Q14247

Q9P2B4

0

binding

up-regulates activity

0.357

CTTNBP2NL interacts with cortactin and targets cortactin to stress fibers.

SIGNOR-261695

Q5JVL4

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.356

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266934

Q8N165

Q05D32

0

dephosphorylation

up-regulates quantity by stabilization

0.356

We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D).

SIGNOR-273773

P22626

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.356

We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,

SIGNOR-268691

Q8N6F7

P43405

0

phosphorylation

up-regulates activity

0.356

Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation.

SIGNOR-273570

Q96P20

Q9Y2R2

0

dephosphorylation

up-regulates activity

0.356

Further, this explains how loss of PTPN22 and subsequent enhanced NLRP3 phosphorylation mediate a decrease in NLRP3 inflammasome activation.|Upon NLRP3 activation, PTPN22 dephosphorylates NLRP3 and thereby protects it from degradation, allowing robust inflammasome activity (summarized in Fig.S6).

SIGNOR-277056

Q00987

P62136

0

dephosphorylation

up-regulates quantity by stabilization

0.356

Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.

SIGNOR-248566

Q13188

P31749

0

phosphorylation

down-regulates

0.356

We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.

SIGNOR-163533

O75628

Q15139

0

phosphorylation

up-regulates activity

0.356

We found that activation of protein kinase D1, a protein kinase downstream of α(1)-adrenergic signaling, leads to direct phosphorylation of Rem1 at Ser18. This results in an increase of the channel activity and plasma membrane expression observed by using a combination of electrophysiology, live cell confocal microscopy, and immunohistochemistry in heterologous expression system and neonatal cardiomyocytes.

SIGNOR-273832

Q12778

Q13237

0

phosphorylation

up-regulates activity

0.356

Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2.

SIGNOR-279564

P17542

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.356

Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively.

SIGNOR-271393

Q01130

Q9UBN7

0

deacetylation

up-regulates

0.356

Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation.

SIGNOR-170590

Q9Y4X5

Q13616

0

binding

up-regulates activity

0.356

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

SIGNOR-268844

O14640

P31431

0

binding

up-regulates

0.356

Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1.

SIGNOR-199632

P43694

P11802

0

phosphorylation

up-regulates activity

0.356

In addition, we have shown that CDK4 can enhance cardiogenic activity of GATA4 (XREF_FIG).|The physical and functional interactions between GATA4 and Cyclin D2 depend on phosphorylation of Ser 160 of GATA4, which can be mediated in vitro by CDK4.

SIGNOR-279148

P08151

O14920

0

phosphorylation

up-regulates activity

0.356

Active IKKbeta promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma.|Herein, we demonstrate that IKKbeta phosphorylates GLI1 in DLBCL.

SIGNOR-279194

P08047

Q01664

0

binding

up-regulates activity

0.356

We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.

SIGNOR-226593

P17480

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.356

MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.

SIGNOR-269644

Q13794

Q00535

0

phosphorylation

down-regulates

0.356

We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase

SIGNOR-170357

O95238

Q9UQ88

0

phosphorylation

down-regulates quantity by destabilization

0.356

In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|

SIGNOR-273022

Q8IV63

Q00535

0

phosphorylation

up-regulates activity

0.356

Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation|

SIGNOR-275544

O15519

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.356

Taken together, our data suggest that CHIP interacts with c-FLIP L in vivo and promotes the ubiquitination of c-FLIP L.|When we knocked down CHIP, c-FLIP L degradation was inhibited after treatment with 17-AAG, which indicated that CHIP modulated c-FLIP L degradation in the NSCLC cell lines.

SIGNOR-278783

P52948

Q08211

0

binding

up-regulates activity

0.356

Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription.

SIGNOR-260954

O15055

Q00987

0

polyubiquitination

down-regulates quantity by destabilization

0.356

We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation.

SIGNOR-277421

Q92519

P23443

0

phosphorylation

down-regulates quantity by destabilization

0.356

Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2.

SIGNOR-275433

P09471

P21918

0

binding

up-regulates activity

0.356

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-257244

Q9UQL6

P34947

0

phosphorylation

down-regulates activity

0.356

GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5.

SIGNOR-279045

P49815

O75592

0

ubiquitination

down-regulates quantity by destabilization

0.356

We show that Pam associates with E2 ubiquitin conjugating enzymes, and tuberin can be ubiquitinated by Pam through its RING finger domain.

SIGNOR-278704

O95251

P06493

0

phosphorylation

up-regulates

0.355

Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.

SIGNOR-160747

P57078

Q13490

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-272708

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

P29317

P31749

0

phosphorylation

up-regulates activity

0.355

As non-canonical EphA2 activation requires phosphorylation of EphA2 at serine 897 by pAkt (Fig.\u00a02b), we sought to determine the effect of PTEN-mediated Akt regulation on invasion.

SIGNOR-279787

P29590

Q6ZNA4

0

polyubiquitination

down-regulates quantity by destabilization

0.355

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-272883

Q14721

P23469

0

dephosphorylation

down-regulates activity

0.355

Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon

SIGNOR-248450

O94761

P06493

0

phosphorylation

up-regulates activity

0.355

During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.

SIGNOR-277375

P51812

P12931

0

phosphorylation

up-regulates

0.355

Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway.

SIGNOR-160052

Q9BST9

Q15139

0

phosphorylation

up-regulates activity

0.355

Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane.

SIGNOR-275511

Q13444

P08631

0

phosphorylation

up-regulates

0.355

Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.

SIGNOR-112919

P06239

P04150

0

binding

up-regulates

0.355

The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation.

SIGNOR-251685

Q15139

P24723

0

phosphorylation

up-regulates

0.355

These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.

SIGNOR-66734

Q03113

Q9H1C0

0

binding

up-regulates activity

0.355

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-257205

P78362

P23443

0

phosphorylation

up-regulates activity

0.355

Altogether, these results identify S6K1-phosphorylated SRPK2 as an essential mediator of IGF1-stimulated SG formation in hPDAC cells.|The nodes of the core SG network are known to contribute to SG formation to varying degrees and it is possible that S6K1-stimulated SRPK2 may impact their contribution; this is consistent with the predicted model whereby SG assembly is subject to regulation by positive and negative cooperativity of extrinsic factors with the core network interactions (14).

SIGNOR-280121

Q9BX46

Q15208

0

phosphorylation

up-regulates activity

0.355

Phosphorylation of Rbm24 by Stk38 is crucial for the maintenance of cardiac sarcomeric gene expression in cardiac cells.|These results indicated that Stk38 increases Rbm24 protein stability probably by interfering with the ubiquitin-proteasome protein degradation pathway.

SIGNOR-278291

Q9NY61

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.355

The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. |DNA damage stabilizes Che-1 protein|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site.

SIGNOR-264415

P12931

P45984

0

phosphorylation

up-regulates activity

0.355

Activation of c-Src by JNK2 was accompanied by the phosphorylation of c-Src on threonine residue (s).|JNK2 directly phosphorylates c-Src and activates its auto phosphorylation.

SIGNOR-279221

P40925

Q86X55

0

acetylation

down-regulates activity

0.355

Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization

SIGNOR-267639