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
P12830	O60315	0	transcriptional regulation	down-regulates quantity by repression	0.487	SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation).	SIGNOR-268950
Q15078	P15882	2	binding	up-regulates	0.337	_-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional	SIGNOR-123439
P48061	P61073	2	binding	up-regulates	0.809	To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells.	SIGNOR-115029
O60260	P00519	0	phosphorylation	down-regulates	0.2	Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function.	SIGNOR-167853
P40429	O43293	0	phosphorylation	up-regulates	0.402	Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro	SIGNOR-182117
Q9ULV8	Q96JA1	2	ubiquitination	down-regulates	0.2	Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation	SIGNOR-127292
Q9Y4G8	O14920	0	phosphorylation	down-regulates quantity by destabilization	0.2	Taken together, these results indicate that IKK\u03b2-dependent phosphorylation of RAPGEF2 is required for RAPGEF2 degradation induced by HGF and mediated by \u03b2TrCP.	SIGNOR-279807
Q92995	P01106	1	deubiquitination	up-regulates quantity by stabilization	0.353	In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation.	SIGNOR-274124
P40763	Q15262	0	dephosphorylation	down-regulates activity	0.374	In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.\|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705).	SIGNOR-277060
P27348	P55040	2	binding	up-regulates quantity by stabilization	0.266	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. (Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261724
Q92793	Q9Y6B2	2	binding	down-regulates activity	0.406	Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity.	SIGNOR-253380
Q14676	O60934	2	binding	up-regulates	0.834	Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1.	SIGNOR-184141
Q96S42	P13385	2	binding	up-regulates activity	0.661	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251937
O75309	P35222	2	binding	up-regulates activity	0.366	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265855
Q13131	Q13085	1	phosphorylation	down-regulates activity	0.7	We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase	SIGNOR-250400
P29322	P20827	2	binding	up-regulates	0.817	Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells.	SIGNOR-154298
P35498	Q92915	2	binding	down-regulates activity	0.361	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-253421
Q96S42	P36896	2	binding	up-regulates activity	0.642	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251939
P63096	P41595	2	binding	up-regulates activity	0.277	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-256743
P17844	P17252	0	phosphorylation	down-regulates activity	0.335	We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity \| In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC	SIGNOR-248896
Q9H093	O43561	1	phosphorylation	down-regulates activity	0.2	Analysis by an in vitro kinase assay revealed that NUAK2 could phosphorylate immunoprecipitated LATS and that this phosphorylation was lost in the LATS double mutant (DM), T246A/S613A (Fig.\u00a0 xref ).\|We showed that phosphorylation of Ser613, located upstream of the KD, adjacent to the MOB binding site and to a lesser extent the N-terminal localized T246, are required for NUAK2 to inhibit LATS.	SIGNOR-280052
Q9BRX9	P27361	2	binding	up-regulates	0.508	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-124473
Q9H3R0	P04908	1	demethylation	down-regulates activity	0.2	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation	SIGNOR-263862
Q13137	Q9UHD2	0	phosphorylation	up-regulates activity	0.795	Furthermore, we found that TBC1D9-regulated TBK1 activation and recruitment of NDP52 and ULK1 complex to damaged mitochondria (Fig.\u00a0 xref ).\|TBK1 can phosphorylate p62, OPTN, and NDP52 to promote selective autophagy by facilitating their interaction with LC3, ubiquitin, and RAB35, respectively xref , xref , xref .	SIGNOR-280151
P23458	P40189	0	null	up-regulates	0.676	Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects.	SIGNOR-202036
O60716	P17252	0	phosphorylation	down-regulates activity	0.251	PKC\u03b1 phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly.\|We surmised that PKCalpha may function to disrupt AJs by signaling dissociation of p120 from VE-cadherin.	SIGNOR-278261
P04637	Q6ZWH5	0	phosphorylation	up-regulates activity	0.256	Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10 directly phosphorylates p53 on Y327, revealing NEK10's unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response.	SIGNOR-273881
Q15797	Q04771	0	phosphorylation	up-regulates activity	0.703	ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif	SIGNOR-251439
P49959	P15927	2	binding	up-regulates	0.2	The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex.	SIGNOR-186648
Q9UKG1	Q15831	2	binding	up-regulates	0.316	In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol.	SIGNOR-186065
P10276	P17612	0	phosphorylation	down-regulates activity	0.405	Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.	SIGNOR-276281
Q9BSJ6	Q8TAS1	0	phosphorylation	up-regulates	0.2	Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats	SIGNOR-192702
Q9BSQ5	O00506	0	phosphorylation	up-regulates	0.5	CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling.	SIGNOR-263144
P08913	Q05655	0	phosphorylation	up-regulates activity	0.533	Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.	SIGNOR-249126
Q4VCS5	Q9GZV5	1	relocalization	down-regulates	0.678	Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.	SIGNOR-201132
P51955	O14777	1	phosphorylation	up-regulates	0.592	Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.	SIGNOR-94322
P06493	P23396	1	phosphorylation	up-regulates	0.362	These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3.	SIGNOR-176131
O14641	Q9NQ66	1	null	up-regulates activity	0.268	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258979
O43660	P30291	0	phosphorylation	down-regulates activity	0.2	These results indicate that WEE1 promotes PRL1 phosphorylation.\|WEE1 promotes PRL1 degradation .	SIGNOR-279579
Q8TD16	P49792	0	relocalization	up-regulates quantity	0.505	We show that the dynein/dynactin adaptor BICD2 is specifically recruited to the NPC in G2phase through a direct interaction with the NPC componentRanBP2.	SIGNOR-259122
Q13635	Q9Y625	2	binding	up-regulates activity	0.35	Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction.	SIGNOR-264031
O00254	P09471	2	binding	up-regulates activity	0.2	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-257234
O14965	Q9Y448	1	phosphorylation	down-regulates activity	0.261	The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation.	SIGNOR-252052
Q9P1A6	P78352	2	binding	up-regulates activity	0.705	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264210
Q8IZQ1	Q13501	2	binding	up-regulates quantity	0.562	We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions.	SIGNOR-266792
Q15835	Q8IVF5	1	phosphorylation	down-regulates activity	0.2	For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ).	SIGNOR-279997
Q93098	Q9NPG1	2	binding	up-regulates	0.625	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132024
Q71U36	Q8NG68	0	tyrosination	down-regulates	0.533	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176912
Q9Y6K9	Q13315	0	phosphorylation	down-regulates activity	0.739	Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export.	SIGNOR-144813
P37840	P67775	0	dephosphorylation	down-regulates activity	0.332	α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129	SIGNOR-248635
Q8N752	P10071	1	phosphorylation	up-regulates	0.333	Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-144554
O15350	P05771	0	phosphorylation	up-regulates activity	0.2	Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.	SIGNOR-276234
Q8N122	O75385	0	phosphorylation	down-regulates activity	0.704	ULK1 phosphorylates RPTOR at S792, S855, and S859.\|When active, ULK1 inhibits MTOR complex 1 through phosphorylation of RPTOR, which has the effect of limiting RPTOR-mediated recruitment of MTOR substrates to MTOR complex 1 [ ].	SIGNOR-278461
P15311	Q5S007	0	phosphorylation	up-regulates activity	0.411	LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.	SIGNOR-279202
O00206	Q99836	2	binding	up-regulates activity	0.771	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-252065
P30556	Q14344	2	binding	up-regulates	0.522	These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction.	SIGNOR-171760
P22914	P02511	2	binding	up-regulates activity	0.538	Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.	SIGNOR-253623
Q01453	P25189	2	binding	up-regulates activity	0.575	Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction.	SIGNOR-251898
P61586	Q13618	0	ubiquitination	down-regulates quantity by destabilization	0.396	BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264238
Q00987	O75417	1	polyubiquitination	down-regulates quantity by destabilization	0.2	DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation	SIGNOR-272729
P18545	P11488	2	binding	down-regulates activity	0.764	In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis.	SIGNOR-260008
O95405	P29590	2	binding	up-regulates	0.574	Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.	SIGNOR-128744
P35813	Q15796	1	dephosphorylation	down-regulates	0.668	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-146919
O94916	P06493	0	phosphorylation	up-regulates	0.2	High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1.	SIGNOR-170882
O60315	P11473	1	transcriptional regulation	up-regulates quantity by expression	0.2	ZEB, a Krüppel-type transcription factor known to repress the transcription of several genes, binds to two sites within the VDR promoter and activates the transcription of this receptor in a cell-specific manner. Transfection of ZEB into SW620 colon carcinoma cells results in an up-regulation of the expression of endogenous VDR, confirming the role of ZEB in the transcriptional activation of the VDR gene.	SIGNOR-268954
P42680	P51813	1	phosphorylation	up-regulates activity	0.332	Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk	SIGNOR-246647
Q13131	Q8NE86	1	phosphorylation	up-regulates activity	0.2	Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). \|In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57	SIGNOR-275547
Q6N021	Q02750	0	phosphorylation	up-regulates quantity by stabilization	0.247	TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11.	SIGNOR-277891
Q969D9	Q9HC73	2	binding	up-regulates	0.924	Human tslp is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human tslp receptor and the il-7r alpha-chain.	SIGNOR-108920
Q38SD2	P17252	0	phosphorylation	up-regulates activity	0.2	PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain.	SIGNOR-276865
P49418	P28482	0	phosphorylation	down-regulates activity	0.265	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-126859
Q9Y3C5	P31749	0	phosphorylation	down-regulates quantity	0.456	Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity	SIGNOR-252558
Q9HCE7	P37173	1	ubiquitination	down-regulates activity	0.615	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195672
O15519	P17252	0	phosphorylation	up-regulates quantity by stabilization	0.2	Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins	SIGNOR-276147
P04150	P31749	0	phosphorylation	down-regulates	0.486	Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus	SIGNOR-252543
Q96FA3	P00533	2	polyubiquitination	up-regulates quantity by stabilization	0.2	EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse.	SIGNOR-277875
Q14680	Q08050	1	phosphorylation	up-regulates activity	0.501	MELK Activates FOXM1 Transcriptional Activity Leading to Upregulation of Mitotic Gene Expression.\|The autoradiogram clearly shows in vitro phosphorylation of FOXM1 by MELK and CDK2 and cyclinA.	SIGNOR-278412
Q9H158	P05556	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.	SIGNOR-269032
P10071	O43791	0	ubiquitination	down-regulates quantity	0.704	RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins	SIGNOR-268861
Q96CA5	Q9NR28	2	binding	down-regulates	0.666	These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases.	SIGNOR-129869
P15336	Q9Y297	0	ubiquitination	down-regulates quantity by destabilization	0.2	Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).	SIGNOR-267830
P42702	Q92520	2	binding	up-regulates activity	0.2	Interleukin-like EMT inducer (ILEI) a cytokine from the FAM3 family, also functions as a ligand for LIFR-gp130 heterodimer and mediates intracellular signal through STAT activation.	SIGNOR-277986
Q16236	P17252	0	phosphorylation	up-regulates	0.536	Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress	SIGNOR-91826
P35555	Q14767	2	binding	up-regulates activity	0.301	LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network.	SIGNOR-251891
Q13464	Q9NRY4	1	phosphorylation	down-regulates activity	0.414	these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells	SIGNOR-276177
P04628	Q9UP38	2	binding	up-regulates activity	0.701	Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)	SIGNOR-217827
Q99942	Q86WV6	1	ubiquitination	down-regulates quantity by destabilization	0.2	The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection.	SIGNOR-271484
P63096	O60755	2	binding	up-regulates activity	0.45	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-256719
Q14940	P32121	0	relocalization	down-regulates activity	0.397	Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)	SIGNOR-275506
P78527	Q14191	1	phosphorylation	up-regulates	0.641	Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.	SIGNOR-203737
P46527	P07948	0	phosphorylation	down-regulates	0.553	We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation.	SIGNOR-172904
P55040	P0DP23	2	binding	up-regulates activity	0.332	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-261726
Q8TDR2	Q05D32	0	dephosphorylation	up-regulates quantity by stabilization	0.282	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-273775
P08246	P01019	1	cleavage	up-regulates activity	0.275	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256313
P31946	P07196	2	binding	down-regulates activity	0.254	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252396
Q96GD4	Q01860	1	phosphorylation	down-regulates activity	0.38	Aurkb phosphorylates Oct4(S229) during G2/M phase, leading to the dissociation of Oct4 from chromatin, whereas PP1 binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition, which resets Oct4-driven transcription for pluripotency and the cell cycle.	SIGNOR-279592
O75051	Q14563	2	binding	up-regulates	0.858	Plexins form stable complexes with neuropilin-1 or -2.	SIGNOR-75168
Q13131	P31749	0	phosphorylation	down-regulates activity	0.292	It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase.	SIGNOR-252739
Q13541	P68400	0	phosphorylation	down-regulates	0.341	Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites.	SIGNOR-98280
Q9HC16	P46934	0	ubiquitination	up-regulates activity	0.284	APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles\|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions.	SIGNOR-278635

P12830

O60315

0

transcriptional regulation

down-regulates quantity by repression

0.487

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

SIGNOR-268950

Q15078

P15882

2

binding

up-regulates

0.337

_-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional

SIGNOR-123439

P48061

P61073

2

binding

up-regulates

0.809

To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells.

SIGNOR-115029

O60260

P00519

0

phosphorylation

down-regulates

0.2

Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function.

SIGNOR-167853

P40429

O43293

0

phosphorylation

up-regulates

0.402

Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro

SIGNOR-182117

Q9ULV8

Q96JA1

2

ubiquitination

down-regulates

0.2

Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation

SIGNOR-127292

Q9Y4G8

O14920

0

phosphorylation

down-regulates quantity by destabilization

0.2

Taken together, these results indicate that IKK\u03b2-dependent phosphorylation of RAPGEF2 is required for RAPGEF2 degradation induced by HGF and mediated by \u03b2TrCP.

SIGNOR-279807

Q92995

P01106

1

deubiquitination

up-regulates quantity by stabilization

0.353

In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation.

SIGNOR-274124

P40763

Q15262

0

dephosphorylation

down-regulates activity

0.374

In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705).

SIGNOR-277060

P27348

P55040

2

binding

up-regulates quantity by stabilization

0.266

In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. (Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase

SIGNOR-261724

Q92793

Q9Y6B2

2

binding

down-regulates activity

0.406

Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity.

SIGNOR-253380

Q14676

O60934

2

binding

up-regulates

0.834

Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1.

SIGNOR-184141

Q96S42

P13385

2

binding

up-regulates activity

0.661

Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.

SIGNOR-251937

O75309

P35222

2

binding

up-regulates activity

0.366

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265855

Q13131

Q13085

1

phosphorylation

down-regulates activity

0.7

We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase

SIGNOR-250400

P29322

P20827

2

binding

up-regulates

0.817

Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells.

SIGNOR-154298

P35498

Q92915

2

binding

down-regulates activity

0.361

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-253421

Q96S42

P36896

2

binding

up-regulates activity

0.642

Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.

SIGNOR-251939

P63096

P41595

2

binding

up-regulates activity

0.277

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-256743

P17844

P17252

0

phosphorylation

down-regulates activity

0.335

We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity | In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC

SIGNOR-248896

Q9H093

O43561

1

phosphorylation

down-regulates activity

0.2

Analysis by an in vitro kinase assay revealed that NUAK2 could phosphorylate immunoprecipitated LATS and that this phosphorylation was lost in the LATS double mutant (DM), T246A/S613A (Fig.\u00a0 xref ).|We showed that phosphorylation of Ser613, located upstream of the KD, adjacent to the MOB binding site and to a lesser extent the N-terminal localized T246, are required for NUAK2 to inhibit LATS.

SIGNOR-280052

Q9BRX9

P27361

2

binding

up-regulates

0.508

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-124473

Q9H3R0

P04908

1

demethylation

down-regulates activity

0.2

As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation

SIGNOR-263862

Q13137

Q9UHD2

0

phosphorylation

up-regulates activity

0.795

Furthermore, we found that TBC1D9-regulated TBK1 activation and recruitment of NDP52 and ULK1 complex to damaged mitochondria (Fig.\u00a0 xref ).|TBK1 can phosphorylate p62, OPTN, and NDP52 to promote selective autophagy by facilitating their interaction with LC3, ubiquitin, and RAB35, respectively xref , xref , xref .

SIGNOR-280151

P23458

P40189

0

null

up-regulates

0.676

Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects.

SIGNOR-202036

O60716

P17252

0

phosphorylation

down-regulates activity

0.251

PKC\u03b1 phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly.|We surmised that PKCalpha may function to disrupt AJs by signaling dissociation of p120 from VE-cadherin.

SIGNOR-278261

P04637

Q6ZWH5

0

phosphorylation

up-regulates activity

0.256

Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10 directly phosphorylates p53 on Y327, revealing NEK10's unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response.

SIGNOR-273881

Q15797

Q04771

0

phosphorylation

up-regulates activity

0.703

ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif

SIGNOR-251439

P49959

P15927

2

binding

up-regulates

0.2

The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex.

SIGNOR-186648

Q9UKG1

Q15831

2

binding

up-regulates

0.316

In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol.

SIGNOR-186065

P10276

P17612

0

phosphorylation

down-regulates activity

0.405

Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.

SIGNOR-276281

Q9BSJ6

Q8TAS1

0

phosphorylation

up-regulates

0.2

Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats

SIGNOR-192702

Q9BSQ5

O00506

0

phosphorylation

up-regulates

0.5

CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling.

SIGNOR-263144

P08913

Q05655

0

phosphorylation

up-regulates activity

0.533

Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.

SIGNOR-249126

Q4VCS5

Q9GZV5

1

relocalization

down-regulates

0.678

Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.

SIGNOR-201132

P51955

O14777

1

phosphorylation

up-regulates

0.592

Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.

SIGNOR-94322

P06493

P23396

1

phosphorylation

up-regulates

0.362

These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3.

SIGNOR-176131

O14641

Q9NQ66

1

null

up-regulates activity

0.268

Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin

SIGNOR-258979

O43660

P30291

0

phosphorylation

down-regulates activity

0.2

These results indicate that WEE1 promotes PRL1 phosphorylation.|WEE1 promotes PRL1 degradation .

SIGNOR-279579

Q8TD16

P49792

0

relocalization

up-regulates quantity

0.505

We show that the dynein/dynactin adaptor BICD2 is specifically recruited to the NPC in G2phase through a direct interaction with the NPC componentRanBP2.

SIGNOR-259122

Q13635

Q9Y625

2

binding

up-regulates activity

0.35

Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction.

SIGNOR-264031

O00254

P09471

2

binding

up-regulates activity

0.2

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-257234

O14965

Q9Y448

1

phosphorylation

down-regulates activity

0.261

The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation.

SIGNOR-252052

Q9P1A6

P78352

2

binding

up-regulates activity

0.705

SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.

SIGNOR-264210

Q8IZQ1

Q13501

2

binding

up-regulates quantity

0.562

We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions.

SIGNOR-266792

Q15835

Q8IVF5

1

phosphorylation

down-regulates activity

0.2

For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ).

SIGNOR-279997

Q93098

Q9NPG1

2

binding

up-regulates

0.625

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

SIGNOR-132024

Q71U36

Q8NG68

0

tyrosination

down-regulates

0.533

Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization

SIGNOR-176912

Q9Y6K9

Q13315

0

phosphorylation

down-regulates activity

0.739

Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export.

SIGNOR-144813

P37840

P67775

0

dephosphorylation

down-regulates activity

0.332

α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129

SIGNOR-248635

Q8N752

P10071

1

phosphorylation

up-regulates

0.333

Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed

SIGNOR-144554

O15350

P05771

0

phosphorylation

up-regulates activity

0.2

Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.

SIGNOR-276234

Q8N122

O75385

0

phosphorylation

down-regulates activity

0.704

ULK1 phosphorylates RPTOR at S792, S855, and S859.|When active, ULK1 inhibits MTOR complex 1 through phosphorylation of RPTOR, which has the effect of limiting RPTOR-mediated recruitment of MTOR substrates to MTOR complex 1 [ ].

SIGNOR-278461

P15311

Q5S007

0

phosphorylation

up-regulates activity

0.411

LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.

SIGNOR-279202

O00206

Q99836

2

binding

up-regulates activity

0.771

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-252065

P30556

Q14344

2

binding

up-regulates

0.522

These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction.

SIGNOR-171760

P22914

P02511

2

binding

up-regulates activity

0.538

Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.

SIGNOR-253623

Q01453

P25189

2

binding

up-regulates activity

0.575

Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction.

SIGNOR-251898

P61586

Q13618

0

ubiquitination

down-regulates quantity by destabilization

0.396

BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.

SIGNOR-264238

Q00987

O75417

1

polyubiquitination

down-regulates quantity by destabilization

0.2

DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation

SIGNOR-272729

P18545

P11488

2

binding

down-regulates activity

0.764

In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis.

SIGNOR-260008

O95405

P29590

2

binding

up-regulates

0.574

Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.

SIGNOR-128744

P35813

Q15796

1

dephosphorylation

down-regulates

0.668

Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.

SIGNOR-146919

O94916

P06493

0

phosphorylation

up-regulates

0.2

High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1.

SIGNOR-170882

O60315

P11473

1

transcriptional regulation

up-regulates quantity by expression

0.2

ZEB, a Krüppel-type transcription factor known to repress the transcription of several genes, binds to two sites within the VDR promoter and activates the transcription of this receptor in a cell-specific manner. Transfection of ZEB into SW620 colon carcinoma cells results in an up-regulation of the expression of endogenous VDR, confirming the role of ZEB in the transcriptional activation of the VDR gene.

SIGNOR-268954

P42680

P51813

1

phosphorylation

up-regulates activity

0.332

Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk

SIGNOR-246647

Q13131

Q8NE86

1

phosphorylation

up-regulates activity

0.2

Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57

SIGNOR-275547

Q6N021

Q02750

0

phosphorylation

up-regulates quantity by stabilization

0.247

TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11.

SIGNOR-277891

Q969D9

Q9HC73

2

binding

up-regulates

0.924

Human tslp is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human tslp receptor and the il-7r alpha-chain.

SIGNOR-108920

Q38SD2

P17252

0

phosphorylation

up-regulates activity

0.2

PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain.

SIGNOR-276865

P49418

P28482

0

phosphorylation

down-regulates activity

0.265

Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.

SIGNOR-126859

Q9Y3C5

P31749

0

phosphorylation

down-regulates quantity

0.456

Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity

SIGNOR-252558

Q9HCE7

P37173

1

ubiquitination

down-regulates activity

0.615

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

SIGNOR-195672

O15519

P17252

0

phosphorylation

up-regulates quantity by stabilization

0.2

Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins

SIGNOR-276147

P04150

P31749

0

phosphorylation

down-regulates

0.486

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

SIGNOR-252543

Q96FA3

P00533

2

polyubiquitination

up-regulates quantity by stabilization

0.2

EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse.

SIGNOR-277875

Q14680

Q08050

1

phosphorylation

up-regulates activity

0.501

MELK Activates FOXM1 Transcriptional Activity Leading to Upregulation of Mitotic Gene Expression.|The autoradiogram clearly shows in vitro phosphorylation of FOXM1 by MELK and CDK2 and cyclinA.

SIGNOR-278412

Q9H158

P05556

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.

SIGNOR-269032

P10071

O43791

0

ubiquitination

down-regulates quantity

0.704

RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins

SIGNOR-268861

Q96CA5

Q9NR28

2

binding

down-regulates

0.666

These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases.

SIGNOR-129869

P15336

Q9Y297

0

ubiquitination

down-regulates quantity by destabilization

0.2

Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).

SIGNOR-267830

P42702

Q92520

2

binding

up-regulates activity

0.2

Interleukin-like EMT inducer (ILEI) a cytokine from the FAM3 family, also functions as a ligand for LIFR-gp130 heterodimer and mediates intracellular signal through STAT activation.

SIGNOR-277986

Q16236

P17252

0

phosphorylation

up-regulates

0.536

Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress

SIGNOR-91826

P35555

Q14767

2

binding

up-regulates activity

0.301

LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network.

SIGNOR-251891

Q13464

Q9NRY4

1

phosphorylation

down-regulates activity

0.414

these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells

SIGNOR-276177

P04628

Q9UP38

2

binding

up-regulates activity

0.701

Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)

SIGNOR-217827

Q99942

Q86WV6

1

ubiquitination

down-regulates quantity by destabilization

0.2

The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection.

SIGNOR-271484

P63096

O60755

2

binding

up-regulates activity

0.45

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-256719

Q14940

P32121

0

relocalization

down-regulates activity

0.397

Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)

SIGNOR-275506

P78527

Q14191

1

phosphorylation

up-regulates

0.641

Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.

SIGNOR-203737

P46527

P07948

0

phosphorylation

down-regulates

0.553

We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation.

SIGNOR-172904

P55040

P0DP23

2

binding

up-regulates activity

0.332

Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.

SIGNOR-261726

Q8TDR2

Q05D32

0

dephosphorylation

up-regulates quantity by stabilization

0.282

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-273775

P08246

P01019

1

cleavage

up-regulates activity

0.275

Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.

SIGNOR-256313

P31946

P07196

2

binding

down-regulates activity

0.254

These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.

SIGNOR-252396

Q96GD4

Q01860

1

phosphorylation

down-regulates activity

0.38

Aurkb phosphorylates Oct4(S229) during G2/M phase, leading to the dissociation of Oct4 from chromatin, whereas PP1 binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition, which resets Oct4-driven transcription for pluripotency and the cell cycle.

SIGNOR-279592

O75051

Q14563

2

binding

up-regulates

0.858

Plexins form stable complexes with neuropilin-1 or -2.

SIGNOR-75168

Q13131

P31749

0

phosphorylation

down-regulates activity

0.292

It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase.

SIGNOR-252739

Q13541

P68400

0

phosphorylation

down-regulates

0.341

Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites.

SIGNOR-98280

Q9HC16

P46934

0

ubiquitination

up-regulates activity

0.284

APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions.

SIGNOR-278635