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
Q9H4A3	Q9UHW9	1	phosphorylation	down-regulates	0.453	We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases.	SIGNOR-187564
Q99878	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265404
P78362	Q07955	1	phosphorylation	up-regulates activity	0.616	In contrast, SRPK1 or SRPK2 overexpression upregulated the phosphorylation and nucleus accumulation of SRSF1.\|Therefore, SRPK1 and SRPK2 may directly phosphorylate SRSF1 and promote it nucleus translocation, subsequently modulate MKNK2 alternative splicing.	SIGNOR-279660
P15173	Q92833	0	transcriptional regulation	down-regulates quantity by repression	0.2	JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells\|Addition of Differentiation Media (DM) to human myoblasts was associated with the induction of MYOG, MYOD and MYL1 and a decrease in JARID2 RNA expression\|Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2 (PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS	SIGNOR-249599
Q15139	Q96P20	1	phosphorylation	up-regulates activity	0.332	PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.\|These data thus suggest that PKD activity at the Golgi is sufficient to activate the NLRP3 inflammasome.	SIGNOR-279428
P78352	Q9P244	2	binding	up-regulates activity	0.775	SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses.	SIGNOR-264095
P27361	P41235	1	phosphorylation	down-regulates activity	0.494	Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4\u03b1.\|Here we have demonstrated that ERK1 is able to phosphorylate HNF4\u03b1 at several serine and threonine residues.	SIGNOR-279070
P06493	O14757	1	phosphorylation	up-regulates	0.411	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175071
Q5VWQ8	Q969H0	0	ubiquitination	down-regulates quantity by destabilization	0.327	DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1	SIGNOR-254774
P48729	P07910	1	phosphorylation	down-regulates	0.354	A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).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-133528
P18031	P06213	2	dephosphorylation	down-regulates activity	0.788	Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor.	SIGNOR-235499
Q9NYY3	Q13627	0	phosphorylation	up-regulates quantity by stabilization	0.313	In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.	SIGNOR-277805
P00519	P09619	2	phosphorylation	down-regulates activity	0.527	C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) \| These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis.	SIGNOR-260931
Q15139	Q12809	1	phosphorylation	down-regulates activity	0.2	Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1.	SIGNOR-277612
P41208	Q15154	0	relocalization	up-regulates	0.531	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-94990
P62993	P21860	2	binding	up-regulates	0.839	All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3.	SIGNOR-121971
Q99558	Q96JP5	0	ubiquitination	up-regulates	0.5	Zfp91 interacts with and promotes the lys(63)-linked ubiquitination of nik and subsequent processing of p100 to p52.	SIGNOR-167331
P48735	Q9NTG7	0	deacetylation	up-regulates	0.657	Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity.	SIGNOR-196617
Q6ZRV2	Q8N752	2	binding	up-regulates quantity	0.2	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273755
Q13950	Q15797	2	binding	up-regulates	0.538	Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation	SIGNOR-195642
P78527	Q9H4A6	1	phosphorylation	up-regulates activity	0.318	In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents	SIGNOR-253558
P50613	O95243	1	phosphorylation	down-regulates activity	0.2	The mechanistic basis for the phase-separation of MED1 is not well understood, and we hypothesize that this may be due to the phosphorylation of MED1 by CDK7 in response to growth stimuli or nuclear translocation of steroid hormone receptors, such as AR.\|Together, we demonstrate that CDK7 inhibition selectively targets MED1 mediated, AR dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC.	SIGNOR-279686
O15294	P98170	0	ubiquitination	down-regulates quantity	0.2	These results demonstrate that XIAP acts as an E3 ubiquitin ligase and ubiquitinates OGT in HCT116 colon cancer cells.\|XIAP promotes the ubiquitin-dependent proteasomal degradation of OGT.	SIGNOR-278800
P38405	Q92847	2	binding	up-regulates activity	0.267	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-256925
P50613	Q00535	1	phosphorylation	up-regulates activity	0.517	In addition, the Cdk7 substrate, CTD of RNAPII, causes a dose-dependent decline in Cdk5 activation by Cdk7.\|Likewise, Cdk7 or cyclin H immunoprecipitate from mouse brain specifically phosphorylates wt Cdk5 at Ser159 and enhances Cdk5 and p25 activity.	SIGNOR-278923
P26358	P49841	0	phosphorylation	down-regulates quantity	0.272	We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation.	SIGNOR-279181
P78352	Q02156	0	phosphorylation	up-regulates quantity	0.285	PKCepsilon directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCepsilon, JNK, or calcium/calmodulin dependent kinase II activity prevented the effects of PKCepsilon activators on PSD-95 phosphorylation.\|These results indicate that PKCepsilon promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.	SIGNOR-280087
Q9NRW4	P03372	1	dephosphorylation	down-regulates activity	0.261	These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway\|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants.	SIGNOR-248827
Q04206	O00255	2	binding	down-regulates	0.462	Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner.	SIGNOR-110067
P00519	P53350	1	phosphorylation	up-regulates activity	0.29	C-ABL can directly phosphorylate PLK1 and activate PLK1. \| The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability.	SIGNOR-260935
P63211	P42336	2	binding	up-regulates	0.432	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-154261
Q13315	Q15831	1	phosphorylation	up-regulates	0.571	We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo.	SIGNOR-92873
Q13470	P19174	2	binding	up-regulates quantity	0.34	GST-protein precipitations from cell lysates confirmed that GST-PLC-gamma1(SH3) associated with endogenously expressed Tnk1.	SIGNOR-273864
Q13315	P62714	0	dephosphorylation	down-regulates activity	0.269	Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.	SIGNOR-248601
P28482	Q15648	1	phosphorylation	up-regulates	0.354	We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription.	SIGNOR-142462
P53004	P05771	1	phosphorylation	up-regulates	0.307	Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex.	SIGNOR-152181
Q15652	P68431	1	demethylation	down-regulates activity	0.2	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265171
Q9H0K1	Q09472	1	phosphorylation	down-regulates activity	0.278	Indeed, overexpression of SIK2 increased p300 phosphorylation at Ser89, while knockdown of SIK2 decreased it (Fig. 4B).	SIGNOR-278368
P0DPK5	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265416
O14640	P35222	2	binding	up-regulates activity	0.806	Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1.	SIGNOR-134285
P23771	P49715	2	binding	down-regulates	0.361	Whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBPα to inhibit its transcriptional activity on the Pparg2 promoter.	SIGNOR-250569
Q8N752	Q2M2I3	2	binding	up-regulates quantity	0.2	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273758
Q13153	P28482	0	phosphorylation	down-regulates activity	0.402	We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal	SIGNOR-249432
P01133	P04626	2	binding	up-regulates	0.791	To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation.	SIGNOR-106497
P30559	P08754	2	binding	up-regulates activity	0.448	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-257178
Q14164	Q92985	1	phosphorylation	up-regulates	0.687	In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3.	SIGNOR-79139
Q15418	P62753	1	phosphorylation	up-regulates	0.589	We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism.	SIGNOR-153622
O43561	P18031	0	dephosphorylation	down-regulates activity	0.504	Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.\|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation	SIGNOR-248403
P06493	P22314	1	phosphorylation	up-regulates	0.405	Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1	SIGNOR-31157
P05231	P40189	2	binding	up-regulates activity	0.869	A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes.	SIGNOR-48041
P61073	P34947	0	phosphorylation	down-regulates quantity	0.459	Conversely, GRK5 knock-down in cells with low WIP1 expression inhibited CXCR4 phosphorylation, increased cell membrane expression of CXCR4, and promoted medulloblastoma growth.\|Transfection of GRK5 into D556-WIP1 cells increased Ser339 phosphorylation of CXCR4 and reduced proliferation.	SIGNOR-279740
Q86YJ5	P05362	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH-IX expression causes ubiquitination and downregulation of ICAM-1 and a short alternative transcript of MARCH-IX lacking the RING-CH domain, termed MARCH-IX RINGless, is shown to act as a positive regulator of MARCH-IX activity.\|MARCH-IX mediates ubiquitination and downregulation of ICAM-1.	SIGNOR-278821
P53396	P12931	0	phosphorylation	up-regulates activity	0.265	We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274107
O15520	P21802	2	binding	up-regulates	0.893	Rfgf-10 bound the kgfr with high affinity comparable to that of kgf	SIGNOR-57380
P68400	Q93009	1	phosphorylation	up-regulates quantity by stabilization	0.372	We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53.	SIGNOR-276530
P68400	Q712K3	1	phosphorylation	up-regulates activity	0.338	Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation	SIGNOR-88050
Q18PE1	P46109	2	binding	up-regulates activity	0.343	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-273848
Q9UI10	P41091	1	guanine nucleotide exchange factor	up-regulates activity	0.698	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269137
P29350	Q13114	1	dephosphorylation	down-regulates activity	0.2	We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446.	SIGNOR-277527
P36873	Q13422	1	dephosphorylation	up-regulates	0.329	Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174865
Q04864	Q14164	0	phosphorylation	up-regulates	0.354	The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.	SIGNOR-148620
O75197	Q9GZT5	2	binding	up-regulates	0.571	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-131619
Q14005	P28482	0	phosphorylation	up-regulates	0.265	The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.	SIGNOR-121852
P28482	O75030	1	phosphorylation	down-regulates	0.705	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation.	SIGNOR-75030
Q13535	Q9NVI1	1	phosphorylation	up-regulates activity	0.623	Alternatively, the locally accumulated ATRIP-ATR might have sufficient activity to phosphorylate FANCI without TOPBP1 stimulation.\|The results described above and our previous studies clearly indicated that FANCI phosphorylation is mediated by ATR kinase in a manner dependent on the FA core complex and FANCD2 protein.	SIGNOR-279320
Q14186	O00716	2	binding	up-regulates activity	0.74	The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3.	SIGNOR-240553
P09874	P17612	0	phosphorylation	up-regulates activity	0.2	In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).	SIGNOR-276652
P12931	P42680	1	phosphorylation	up-regulates activity	0.32	The proximal event following T cell-APC synapse formation is immediate activation of several signaling molecules: The Src kinase phosphorylates and activates Tec tyrosine kinases, which then activate PLC-\u03b3 that is required for IP 3 generation to sustain intracellular calcium flux.	SIGNOR-280135
P17542	P17612	0	phosphorylation	down-regulates	0.2	Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis.	SIGNOR-195987
P12755	Q13485	2	binding	down-regulates activity	0.821	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236074
P23470	P53667	1	dephosphorylation	down-regulates activity	0.26	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254711
P49137	O75925	1	phosphorylation	up-regulates	0.2	T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity.	SIGNOR-199944
P28222	P63096	2	binding	up-regulates activity	0.467	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-256720
P49407	P12931	0	phosphorylation	down-regulates	0.684	Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.	SIGNOR-154564
Q14157	P35226	2	binding	up-regulates activity	0.514	We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex	SIGNOR-261315
P43403	Q12959	0	phosphorylation	up-regulates activity	0.53	Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation.	SIGNOR-274142
P67775	Q02750	1	dephosphorylation	down-regulates	0.559	In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a.	SIGNOR-166649
P17612	P53396	1	phosphorylation	up-regulates activity	0.309	Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)	SIGNOR-250328
P15923	Q02535	2	binding	down-regulates activity	0.53	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241134
P28482	Q8IW41	1	phosphorylation	up-regulates	0.48	Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4.	SIGNOR-58127
Q9GZQ4	O95837	2	binding	up-regulates activity	0.435	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-257292
P25963	Q15349	0	phosphorylation	down-regulates	0.267	Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation.	SIGNOR-164790
P31749	Q9H4A3	1	phosphorylation	up-regulates	0.393	Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt.	SIGNOR-252481
P38405	P35408	2	binding	up-regulates activity	0.25	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-256903
Q04759	Q8IVH8	0	phosphorylation	up-regulates	0.38	We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling.	SIGNOR-176744
Q8TDC3	P30305	1	phosphorylation	down-regulates	0.506	Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-124839
Q15306	P12931	0	phosphorylation	up-regulates activity	0.273	Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation.\|We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target B cell integration cluster in Epstein-Barr virus-transformed cells.	SIGNOR-279287
P10644	O60548	0	transcriptional regulation	up-regulates quantity by expression	0.2	Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold	SIGNOR-261605
O14965	P04637	1	phosphorylation	up-regulates activity	0.778	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-120836
O60331	P12931	0	phosphorylation	up-regulates	0.285	Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation.	SIGNOR-134459
Q96Q27	O75369	2	binding	down-regulates quantity by destabilization	0.416	Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation. Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb.	SIGNOR-271795
P35222	P45984	0	phosphorylation	up-regulates	0.671	Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt.	SIGNOR-178258
Q05397	P46108	0	phosphorylation	up-regulates activity	0.733	Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression \| Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II.	SIGNOR-250777
O00192	P12830	2	binding	up-regulates quantity by stabilization	0.422	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252133
O00712	Q9Y6N7	1	transcriptional regulation	up-regulates quantity	0.246	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268900
O14733	Q12852	0	phosphorylation	up-regulates activity	0.556	Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels	SIGNOR-279630
Q06609	Q00341	2	binding	up-regulates activity	0.2	We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites.	SIGNOR-266697
Q9Y243	O95990	2	binding	up-regulates	0.2	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81800
P09471	Q92633	2	binding	up-regulates activity	0.435	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-256975
P50552	Q70E73	2	binding	up-regulates activity	0.578	Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.	SIGNOR-268426

Q9H4A3

Q9UHW9

1

phosphorylation

down-regulates

0.453

We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases.

SIGNOR-187564

Q99878

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265404

P78362

Q07955

1

phosphorylation

up-regulates activity

0.616

In contrast, SRPK1 or SRPK2 overexpression upregulated the phosphorylation and nucleus accumulation of SRSF1.|Therefore, SRPK1 and SRPK2 may directly phosphorylate SRSF1 and promote it nucleus translocation, subsequently modulate MKNK2 alternative splicing.

SIGNOR-279660

P15173

Q92833

0

transcriptional regulation

down-regulates quantity by repression

0.2

JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells|Addition of Differentiation Media (DM) to human myoblasts was associated with the induction of MYOG, MYOD and MYL1 and a decrease in JARID2 RNA expression|Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2 (PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS

SIGNOR-249599

Q15139

Q96P20

1

phosphorylation

up-regulates activity

0.332

PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.|These data thus suggest that PKD activity at the Golgi is sufficient to activate the NLRP3 inflammasome.

SIGNOR-279428

P78352

Q9P244

2

binding

up-regulates activity

0.775

SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses.

SIGNOR-264095

P27361

P41235

1

phosphorylation

down-regulates activity

0.494

Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4\u03b1.|Here we have demonstrated that ERK1 is able to phosphorylate HNF4\u03b1 at several serine and threonine residues.

SIGNOR-279070

P06493

O14757

1

phosphorylation

up-regulates

0.411

Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency

SIGNOR-175071

Q5VWQ8

Q969H0

0

ubiquitination

down-regulates quantity by destabilization

0.327

DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1

SIGNOR-254774

P48729

P07910

1

phosphorylation

down-regulates

0.354

A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).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-133528

P18031

P06213

2

dephosphorylation

down-regulates activity

0.788

Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor.

SIGNOR-235499

Q9NYY3

Q13627

0

phosphorylation

up-regulates quantity by stabilization

0.313

In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.

SIGNOR-277805

P00519

P09619

2

phosphorylation

down-regulates activity

0.527

C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) | These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis.

SIGNOR-260931

Q15139

Q12809

1

phosphorylation

down-regulates activity

0.2

Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1.

SIGNOR-277612

P41208

Q15154

0

relocalization

up-regulates

0.531

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

SIGNOR-94990

P62993

P21860

2

binding

up-regulates

0.839

All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3.

SIGNOR-121971

Q99558

Q96JP5

0

ubiquitination

up-regulates

0.5

Zfp91 interacts with and promotes the lys(63)-linked ubiquitination of nik and subsequent processing of p100 to p52.

SIGNOR-167331

P48735

Q9NTG7

0

deacetylation

up-regulates

0.657

Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity.

SIGNOR-196617

Q6ZRV2

Q8N752

2

binding

up-regulates quantity

0.2

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273755

Q13950

Q15797

2

binding

up-regulates

0.538

Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation

SIGNOR-195642

P78527

Q9H4A6

1

phosphorylation

up-regulates activity

0.318

In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents

SIGNOR-253558

P50613

O95243

1

phosphorylation

down-regulates activity

0.2

The mechanistic basis for the phase-separation of MED1 is not well understood, and we hypothesize that this may be due to the phosphorylation of MED1 by CDK7 in response to growth stimuli or nuclear translocation of steroid hormone receptors, such as AR.|Together, we demonstrate that CDK7 inhibition selectively targets MED1 mediated, AR dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC.

SIGNOR-279686

O15294

P98170

0

ubiquitination

down-regulates quantity

0.2

These results demonstrate that XIAP acts as an E3 ubiquitin ligase and ubiquitinates OGT in HCT116 colon cancer cells.|XIAP promotes the ubiquitin-dependent proteasomal degradation of OGT.

SIGNOR-278800

P38405

Q92847

2

binding

up-regulates activity

0.267

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-256925

P50613

Q00535

1

phosphorylation

up-regulates activity

0.517

In addition, the Cdk7 substrate, CTD of RNAPII, causes a dose-dependent decline in Cdk5 activation by Cdk7.|Likewise, Cdk7 or cyclin H immunoprecipitate from mouse brain specifically phosphorylates wt Cdk5 at Ser159 and enhances Cdk5 and p25 activity.

SIGNOR-278923

P26358

P49841

0

phosphorylation

down-regulates quantity

0.272

We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation.

SIGNOR-279181

P78352

Q02156

0

phosphorylation

up-regulates quantity

0.285

PKCepsilon directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCepsilon, JNK, or calcium/calmodulin dependent kinase II activity prevented the effects of PKCepsilon activators on PSD-95 phosphorylation.|These results indicate that PKCepsilon promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.

SIGNOR-280087

Q9NRW4

P03372

1

dephosphorylation

down-regulates activity

0.261

These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants.

SIGNOR-248827

Q04206

O00255

2

binding

down-regulates

0.462

Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner.

SIGNOR-110067

P00519

P53350

1

phosphorylation

up-regulates activity

0.29

C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability.

SIGNOR-260935

P63211

P42336

2

binding

up-regulates

0.432

Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt

SIGNOR-154261

Q13315

Q15831

1

phosphorylation

up-regulates

0.571

We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo.

SIGNOR-92873

Q13470

P19174

2

binding

up-regulates quantity

0.34

GST-protein precipitations from cell lysates confirmed that GST-PLC-gamma1(SH3) associated with endogenously expressed Tnk1.

SIGNOR-273864

Q13315

P62714

0

dephosphorylation

down-regulates activity

0.269

Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.

SIGNOR-248601

P28482

Q15648

1

phosphorylation

up-regulates

0.354

We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription.

SIGNOR-142462

P53004

P05771

1

phosphorylation

up-regulates

0.307

Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex.

SIGNOR-152181

Q15652

P68431

1

demethylation

down-regulates activity

0.2

We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.

SIGNOR-265171

Q9H0K1

Q09472

1

phosphorylation

down-regulates activity

0.278

Indeed, overexpression of SIK2 increased p300 phosphorylation at Ser89, while knockdown of SIK2 decreased it (Fig. 4B).

SIGNOR-278368

P0DPK5

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265416

O14640

P35222

2

binding

up-regulates activity

0.806

Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1.

SIGNOR-134285

P23771

P49715

2

binding

down-regulates

0.361

Whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBPα to inhibit its transcriptional activity on the Pparg2 promoter.

SIGNOR-250569

Q8N752

Q2M2I3

2

binding

up-regulates quantity

0.2

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273758

Q13153

P28482

0

phosphorylation

down-regulates activity

0.402

We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal

SIGNOR-249432

P01133

P04626

2

binding

up-regulates

0.791

To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation.

SIGNOR-106497

P30559

P08754

2

binding

up-regulates activity

0.448

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-257178

Q14164

Q92985

1

phosphorylation

up-regulates

0.687

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

SIGNOR-79139

Q15418

P62753

1

phosphorylation

up-regulates

0.589

We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism.

SIGNOR-153622

O43561

P18031

0

dephosphorylation

down-regulates activity

0.504

Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation

SIGNOR-248403

P06493

P22314

1

phosphorylation

up-regulates

0.405

Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1

SIGNOR-31157

P05231

P40189

2

binding

up-regulates activity

0.869

A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes.

SIGNOR-48041

P61073

P34947

0

phosphorylation

down-regulates quantity

0.459

Conversely, GRK5 knock-down in cells with low WIP1 expression inhibited CXCR4 phosphorylation, increased cell membrane expression of CXCR4, and promoted medulloblastoma growth.|Transfection of GRK5 into D556-WIP1 cells increased Ser339 phosphorylation of CXCR4 and reduced proliferation.

SIGNOR-279740

Q86YJ5

P05362

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH-IX expression causes ubiquitination and downregulation of ICAM-1 and a short alternative transcript of MARCH-IX lacking the RING-CH domain, termed MARCH-IX RINGless, is shown to act as a positive regulator of MARCH-IX activity.|MARCH-IX mediates ubiquitination and downregulation of ICAM-1.

SIGNOR-278821

P53396

P12931

0

phosphorylation

up-regulates activity

0.265

We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.

SIGNOR-274107

O15520

P21802

2

binding

up-regulates

0.893

Rfgf-10 bound the kgfr with high affinity comparable to that of kgf

SIGNOR-57380

P68400

Q93009

1

phosphorylation

up-regulates quantity by stabilization

0.372

We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53.

SIGNOR-276530

P68400

Q712K3

1

phosphorylation

up-regulates activity

0.338

Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation

SIGNOR-88050

Q18PE1

P46109

2

binding

up-regulates activity

0.343

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-273848

Q9UI10

P41091

1

guanine nucleotide exchange factor

up-regulates activity

0.698

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

SIGNOR-269137

P29350

Q13114

1

dephosphorylation

down-regulates activity

0.2

We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446.

SIGNOR-277527

P36873

Q13422

1

dephosphorylation

up-regulates

0.329

Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway

SIGNOR-174865

Q04864

Q14164

0

phosphorylation

up-regulates

0.354

The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.

SIGNOR-148620

O75197

Q9GZT5

2

binding

up-regulates

0.571

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-131619

Q14005

P28482

0

phosphorylation

up-regulates

0.265

The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.

SIGNOR-121852

P28482

O75030

1

phosphorylation

down-regulates

0.705

The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation.

SIGNOR-75030

Q13535

Q9NVI1

1

phosphorylation

up-regulates activity

0.623

Alternatively, the locally accumulated ATRIP-ATR might have sufficient activity to phosphorylate FANCI without TOPBP1 stimulation.|The results described above and our previous studies clearly indicated that FANCI phosphorylation is mediated by ATR kinase in a manner dependent on the FA core complex and FANCD2 protein.

SIGNOR-279320

Q14186

O00716

2

binding

up-regulates activity

0.74

The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3.

SIGNOR-240553

P09874

P17612

0

phosphorylation

up-regulates activity

0.2

In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).

SIGNOR-276652

P12931

P42680

1

phosphorylation

up-regulates activity

0.32

The proximal event following T cell-APC synapse formation is immediate activation of several signaling molecules: The Src kinase phosphorylates and activates Tec tyrosine kinases, which then activate PLC-\u03b3 that is required for IP 3 generation to sustain intracellular calcium flux.

SIGNOR-280135

P17542

P17612

0

phosphorylation

down-regulates

0.2

Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis.

SIGNOR-195987

P12755

Q13485

2

binding

down-regulates activity

0.821

The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway

SIGNOR-236074

P23470

P53667

1

dephosphorylation

down-regulates activity

0.26

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

SIGNOR-254711

P49137

O75925

1

phosphorylation

up-regulates

0.2

T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity.

SIGNOR-199944

P28222

P63096

2

binding

up-regulates activity

0.467

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-256720

P49407

P12931

0

phosphorylation

down-regulates

0.684

Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.

SIGNOR-154564

Q14157

P35226

2

binding

up-regulates activity

0.514

We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex

SIGNOR-261315

P43403

Q12959

0

phosphorylation

up-regulates activity

0.53

Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation.

SIGNOR-274142

P67775

Q02750

1

dephosphorylation

down-regulates

0.559

In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a.

SIGNOR-166649

P17612

P53396

1

phosphorylation

up-regulates activity

0.309

Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)

SIGNOR-250328

P15923

Q02535

2

binding

down-regulates activity

0.53

All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-241134

P28482

Q8IW41

1

phosphorylation

up-regulates

0.48

Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4.

SIGNOR-58127

Q9GZQ4

O95837

2

binding

up-regulates activity

0.435

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-257292

P25963

Q15349

0

phosphorylation

down-regulates

0.267

Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation.

SIGNOR-164790

P31749

Q9H4A3

1

phosphorylation

up-regulates

0.393

Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt.

SIGNOR-252481

P38405

P35408

2

binding

up-regulates activity

0.25

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-256903

Q04759

Q8IVH8

0

phosphorylation

up-regulates

0.38

We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling.

SIGNOR-176744

Q8TDC3

P30305

1

phosphorylation

down-regulates

0.506

Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3

SIGNOR-124839

Q15306

P12931

0

phosphorylation

up-regulates activity

0.273

Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation.|We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target B cell integration cluster in Epstein-Barr virus-transformed cells.

SIGNOR-279287

P10644

O60548

0

transcriptional regulation

up-regulates quantity by expression

0.2

Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold

SIGNOR-261605

O14965

P04637

1

phosphorylation

up-regulates activity

0.778

The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A

SIGNOR-120836

O60331

P12931

0

phosphorylation

up-regulates

0.285

Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation.

SIGNOR-134459

Q96Q27

O75369

2

binding

down-regulates quantity by destabilization

0.416

Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation. Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb.

SIGNOR-271795

P35222

P45984

0

phosphorylation

up-regulates

0.671

Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt.

SIGNOR-178258

Q05397

P46108

0

phosphorylation

up-regulates activity

0.733

Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II.

SIGNOR-250777

O00192

P12830

2

binding

up-regulates quantity by stabilization

0.422

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

SIGNOR-252133

O00712

Q9Y6N7

1

transcriptional regulation

up-regulates quantity

0.246

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268900

O14733

Q12852

0

phosphorylation

up-regulates activity

0.556

Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels

SIGNOR-279630

Q06609

Q00341

2

binding

up-regulates activity

0.2

We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites.

SIGNOR-266697

Q9Y243

O95990

2

binding

up-regulates

0.2

Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation

SIGNOR-81800

P09471

Q92633

2

binding

up-regulates activity

0.435

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-256975

P50552

Q70E73

2

binding

up-regulates activity

0.578

Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.

SIGNOR-268426