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
Q92574	P53350	0	phosphorylation	down-regulates quantity by destabilization	0.467	The Hsp90 client Plk1 phosphorylates Sgt1, which had a positive impact on Sgt1 function, whereas phosphorylation of Tsc1 by Plk1 led to its ubiquitination and degradation.	SIGNOR-280072
O75151	P68431	1	demethylation	down-regulates activity	0.2	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264521
Q9Y5B0	P68400	0	phosphorylation	down-regulates activity	0.373	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.\| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. \| Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified	SIGNOR-250844
Q9UGP8	P67870	0	phosphorylation	up-regulates activity	0.2	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265270
P62136	Q13422	1	dephosphorylation	up-regulates	0.279	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-174859
Q13535	O75943	1	phosphorylation	up-regulates activity	0.858	Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival.	SIGNOR-111248
Q9UI33	Q92914	2	binding	down-regulates activity	0.2	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-253438
O43524	Q9HBY8	0	phosphorylation	down-regulates activity	0.521	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)\|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-249130
Q9UQK1	Q6VVB1	0	ubiquitination	down-regulates quantity by destabilization	0.741	We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.	SIGNOR-276238
P01574	P03209	0	transcriptional regulation	down-regulates quantity by repression	0.2	Epstein-Barr Virus BRLF1 Inhibits Transcription of IRF3 and IRF7 and Suppresses Induction of Interferon-β. These results suggest that EBV Rta is capable of regulating the activation of the IFN-β promoter.	SIGNOR-266646
P12814	Q9UPX8	0	relocalization	up-regulates activity	0.297	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264584
P60484	P60484	2	dephosphorylation	up-regulates activity	0.2	Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.\|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites	SIGNOR-248545
P15502	Q9UBX5	2	binding	up-regulates activity	0.761	The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin.	SIGNOR-252137
Q15466	O15516	0	transcriptional regulation	up-regulates quantity by expression	0.388	CLOCK knockdown activated MTP promoter and reduced small heterodimer partner (SHP, NROB2). CLOCK upregulated SHP by binding to its E box.	SIGNOR-253698
Q02078	Q15759	0	phosphorylation	up-regulates activity	0.533	In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.	SIGNOR-280024
P06213	P42345	0	phosphorylation	up-regulates activity	0.391	Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively.\|Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR and InsR.	SIGNOR-280045
O94782	Q8TAF3	2	binding	up-regulates activity	0.946	In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM).	SIGNOR-263274
P52797	P54764	2	binding	up-regulates	0.826	Eph receptors are activated by their ligands, which are membrane-anchored molecules	SIGNOR-52315
Q02156	P18507	1	phosphorylation	down-regulates activity	0.233	Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.	SIGNOR-263174
P21728	P08754	2	binding	up-regulates activity	0.282	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-257181
Q99075	P08254	0	cleavage	up-regulates	0.517	It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor.	SIGNOR-83339
O00533	P16157	1	relocalization	up-regulates quantity	0.532	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266724
P04637	O75182	2	binding	down-regulates activity	0.497	The present study shows that under bleomycin-induced stress, expression of Sin3B gets up-regulated and it gets recruited by p53 at its target promoters. Knockdown of Sin3B leads to impaired negative regulation of p53 target genes and thus exemplifies Sin3B as a critical player in down-regulation of p53 subset target genes.	SIGNOR-266776
O15164	P10275	2	binding	up-regulates	0.396	We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar	SIGNOR-189113
Q92888	Q14344	2	binding	up-regulates activity	0.608	It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho	SIGNOR-256521
P10636	P49840	0	phosphorylation	down-regulates	0.429	Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.	SIGNOR-60651
P10588	Q05655	0	phosphorylation	down-regulates	0.2	Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.	SIGNOR-180017
Q13557	Q14571	1	phosphorylation	down-regulates activity	0.308	Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability.	SIGNOR-262692
P51452	P43405	0	phosphorylation	up-regulates activity	0.363	ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).	SIGNOR-275999
P50750	P35813	0	dephosphorylation	down-regulates activity	0.493	Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function	SIGNOR-248490
P48454	Q13469	1	dephosphorylation	up-regulates activity	0.408	NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248512
P53350	Q99640	1	phosphorylation	down-regulates activity	0.721	Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site.	SIGNOR-263096
Q969Q6	P53041	2	binding	up-regulates activity	0.346	Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function	SIGNOR-272480
Q9NVW2	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.2	Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM.\|Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter.	SIGNOR-268980
P04637	Q13362	0	dephosphorylation	up-regulates quantity by stabilization	0.611	Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation.	SIGNOR-268154
P54792	P05771	2	binding	up-regulates	0.2	Taken together, these results suggest that site-specific dvl2 phosphorylation is required for dvl2 association with pkc_. This interaction is likely to be one of the mechanisms essential for wnt3a-dependent neurite outgrowth.	SIGNOR-199457
Q9P2J3	Q96GD4	2	binding	up-regulates activity	0.71	Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis.	SIGNOR-271658
P00519	Q92918	1	phosphorylation	up-regulates activity	0.379	C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD	SIGNOR-251429
Q01082	Q8NG27	0	ubiquitination	down-regulates	0.403	The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it.	SIGNOR-141216
Q02952	P17612	2	relocalization	up-regulates activity	0.2	A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor.	SIGNOR-271835
Q96A00	O75116	0	phosphorylation	up-regulates activity	0.413	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.\| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].	SIGNOR-96696
Q92838	Q9UNE0	2	binding	up-regulates	0.751	Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain.	SIGNOR-161109
P01116	P21359	2	binding	down-regulates activity	0.721	Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.	SIGNOR-273661
Q9NPH3	P01584	2	binding	up-regulates	0.867	The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri).	SIGNOR-61744
Q07869	P28702	2	binding	up-regulates	0.564	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105448
P25098	P30559	1	phosphorylation	down-regulates activity	0.2	Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization	SIGNOR-270329
Q8N157	P54257	2	binding	up-regulates activity	0.549	Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis.	SIGNOR-269081
P60484	P06239	0	phosphorylation	up-regulates	0.374	Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo.	SIGNOR-116499
P19174	O43561	2	binding	up-regulates activity	0.808	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246060
Q9Y4H4	P62873	2	binding	down-regulates quantity by destabilization	0.385	GPSM3 was found not only to modulate heterotrimeric G-protein subunit signaling through its two active GoLoco motifs, but also to affect monomeric Gbeta subunit biosynthesis and stability\|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.	SIGNOR-264865
Q13049	Q86U86	1	ubiquitination	down-regulates quantity by destabilization	0.2	TRIM32 ubiquitination of PB1 leads to its protein degradation.	SIGNOR-278735
O60664	P20645	1	relocalization	up-regulates activity	0.73	TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.	SIGNOR-253093
Q00526	P18846	1	phosphorylation	up-regulates	0.2	Cyclin-dependent kinase 3-mediated activating transcription factor 1 phosphorylation enhances cell transformationwe found that cdk3 phosphorylates activating transcription factor 1 (atf1) at serine 63 and enhances the transactivation and transcriptional activities of atf1.	SIGNOR-180920
P30679	P28335	2	binding	up-regulates activity	0.503	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-257355
P41968	P01189	2	binding	up-regulates activity	0.759	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268705
P31751	O95988	2	binding	up-regulates	0.56	In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.	SIGNOR-81716
P36956	P54646	0	phosphorylation	down-regulates	0.328	Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372	SIGNOR-173031
O43521	Q16539	0	phosphorylation	down-regulates quantity by destabilization	0.32	Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination.	SIGNOR-260442
Q00535	Q9UKV5	1	phosphorylation	down-regulates quantity by destabilization	0.248	We found that GP78 expression is decreased in MPTP-based cellular and animal PD models, and CDK5 directly phosphorylated GP78 at Ser516, which promoted the ubiquitination and degradation of GP78.	SIGNOR-277356
P19838	Q9UKL3	2	binding	up-regulates	0.246	In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex.	SIGNOR-177104
Q96M98	P0DMV9	2	binding	up-regulates quantity by stabilization	0.2	Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo.	SIGNOR-272891
P63096	Q9GZQ6	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-256708
Q9H4B4	Q07817	1	phosphorylation	up-regulates	0.391	Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest.	SIGNOR-172230
O75385	Q7Z3C6	1	phosphorylation	up-regulates activity	0.582	Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation.	SIGNOR-266369
Q9GZQ6	O15130	2	binding	up-regulates	0.747	Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems	SIGNOR-82916
P41221	P34925	2	binding	up-regulates	0.784	Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells.	SIGNOR-258970
P04637	Q9H2X6	0	phosphorylation	up-regulates	0.797	Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation.	SIGNOR-151930
P08575	P19784	0	phosphorylation	up-regulates activity	0.434	Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.	SIGNOR-251031
P53667	Q16566	0	phosphorylation	up-regulates activity	0.256	An active form of CaMKIV but not CaMKI enhanced Thr 508 phosphorylation of LIMK1 and increased the kinase activity of LIMK1.\|Taken together, our results suggest that LIMK1 mediated cofilin phosphorylation is critical for ionomycin induced neurite outgrowth and that CaMKIV mediates ionomycin induced LIMK1 activation.	SIGNOR-280201
P06730	P67775	0	dephosphorylation	down-regulates	0.347	A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function.	SIGNOR-168306
P55347	P49639	2	binding	up-regulates activity	0.588	Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding.	SIGNOR-220242
Q13261	P43405	0	phosphorylation	up-regulates activity	0.329	Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells	SIGNOR-246556
Q13158	O14965	0	phosphorylation	up-regulates	0.343	Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194	SIGNOR-176739
Q6UY11	P46531	2	binding	down-regulates activity	0.29	Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.	SIGNOR-219377
Q96KG7	O95477	2	binding	up-regulates activity	0.332	ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.	SIGNOR-265165
P01138	P07996	2	binding	up-regulates	0.278	We have identified a mechanism for the activation of latent tgf-beta that involves binding of the secreted and extracellular matrix protein, thrombospondin-1 (tsp-1), to the latent precursor.	SIGNOR-75624
Q9Y2Z0	P53350	0	phosphorylation	up-regulates activity	0.437	Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment\|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone	SIGNOR-265222
Q6ZN44	P43146	2	binding	down-regulates activity	0.661	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268164
Q9H2X6	O00257	1	phosphorylation	up-regulates activity	0.423	In addition, HIPK2 phosphorylates Pc2 at several sites, including threonine 495.	SIGNOR-278484
Q9NR09	P42574	2	binding	down-regulates	0.464	Bruce binds and thereby inhibits caspases, in particular effector caspase-3.	SIGNOR-125956
P45985	O15264	1	phosphorylation	up-regulates activity	0.459	p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273956
Q92837	P17612	0	phosphorylation	down-regulates	0.2	Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription.	SIGNOR-149689
P03372	O96013	0	phosphorylation	up-regulates activity	0.277	Further, PAK4 phosphorylated ER\u03b1-Ser305, a phosphorylation event needed for the PAK4 activation of ER\u03b1-dependent transcription.\|Further, PAK4 phosphorylated ERalpha-Ser305, a phosphorylation event needed for the PAK4 activation of ERalpha dependent transcription.	SIGNOR-279472
Q13467	Q13145	2	binding	up-regulates	0.583	These data together suggest that bambi may form a ternary coreceptor complex with fzd5 and lrp6	SIGNOR-23040
Q9UQM7	Q12959	1	phosphorylation	down-regulates activity	0.649	Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. \| We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII.	SIGNOR-250618
P07384	P55085	1	cleavage	down-regulates activity	0.298	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263580
P51784	P68104	1	deubiquitination	up-regulates activity	0.2	USP11 interacted with and deubiquitinated eEF1A1 on Lys439, thereby inhibiting its ubiquitin-mediated degradation. Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription	SIGNOR-278107
P11161	O00308	0	ubiquitination	down-regulates quantity	0.372	The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination\|AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death.	SIGNOR-268849
O75385	P19367	1	phosphorylation	up-regulates activity	0.257	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274033
O60674	Q9UQQ2	2	binding	down-regulates activity	0.643	we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions.	SIGNOR-260075
Q04206	P48729	0	phosphorylation	up-regulates activity	0.2	These data strongly suggested that CKI phosphorylated Ser-316 of p65. Our data suggested that phosphorylation of p65 on Ser-316 controls the activity and function of NF-κB. Importantly, we found that phosphorylation at the novel Ser-316 site and other two known phosphorylation sites, Ser-529 and Ser-536, either individually or cooperatively, regulated distinct groups of NF-κB-dependent genes, suggesting the unique role of each individual phosphorylation site on NF-κB-dependent gene regulation.	SIGNOR-276916
P35222	P22223	2	binding	up-regulates activity	0.851	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265865
Q9HC29	P0DMV8	2	binding	up-regulates quantity by stabilization	0.256	The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease.	SIGNOR-252416
Q6JBY9	P45983	0	phosphorylation	down-regulates activity	0.286	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263085
Q96P68	P63092	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 ‚â• -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 ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256770
O15197	P29317	2	binding	down-regulates activity	0.422	EphB6 is frequently silenced in invasive and metastatic cancers; however, its role in cancer progression is poorly understood. Here we show that EphB6 interacts with EphA2 and suppresses EphA2-mediated promotion of anoikis resistance in MCF7 breast cancer cells.	SIGNOR-273853
Q9UQM7	P16949	1	phosphorylation	down-regulates	0.403	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.	SIGNOR-149640
Q14493	Q8N257	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265388
Q9BPV8	Q14344	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-257299
Q96PU5	Q9NY46	1	ubiquitination	down-regulates quantity by destabilization	0.283	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253464

Q92574

P53350

0

phosphorylation

down-regulates quantity by destabilization

0.467

The Hsp90 client Plk1 phosphorylates Sgt1, which had a positive impact on Sgt1 function, whereas phosphorylation of Tsc1 by Plk1 led to its ubiquitination and degradation.

SIGNOR-280072

O75151

P68431

1

demethylation

down-regulates activity

0.2

PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.

SIGNOR-264521

Q9Y5B0

P68400

0

phosphorylation

down-regulates activity

0.373

We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified

SIGNOR-250844

Q9UGP8

P67870

0

phosphorylation

up-regulates activity

0.2

Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.

SIGNOR-265270

P62136

Q13422

1

dephosphorylation

up-regulates

0.279

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-174859

Q13535

O75943

1

phosphorylation

up-regulates activity

0.858

Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival.

SIGNOR-111248

Q9UI33

Q92914

2

binding

down-regulates activity

0.2

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-253438

O43524

Q9HBY8

0

phosphorylation

down-regulates activity

0.521

Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.

SIGNOR-249130

Q9UQK1

Q6VVB1

0

ubiquitination

down-regulates quantity by destabilization

0.741

We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.

SIGNOR-276238

P01574

P03209

0

transcriptional regulation

down-regulates quantity by repression

0.2

Epstein-Barr Virus BRLF1 Inhibits Transcription of IRF3 and IRF7 and Suppresses Induction of Interferon-β. These results suggest that EBV Rta is capable of regulating the activation of the IFN-β promoter.

SIGNOR-266646

P12814

Q9UPX8

0

relocalization

up-regulates activity

0.297

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264584

P60484

2

dephosphorylation

up-regulates activity

0.2

Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites

SIGNOR-248545

P15502

Q9UBX5

2

binding

up-regulates activity

0.761

The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin.

SIGNOR-252137

Q15466

O15516

0

transcriptional regulation

up-regulates quantity by expression

0.388

CLOCK knockdown activated MTP promoter and reduced small heterodimer partner (SHP, NROB2). CLOCK upregulated SHP by binding to its E box.

SIGNOR-253698

Q02078

Q15759

0

phosphorylation

up-regulates activity

0.533

In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.

SIGNOR-280024

P06213

P42345

0

phosphorylation

up-regulates activity

0.391

Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively.|Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR and InsR.

SIGNOR-280045

O94782

Q8TAF3

2

binding

up-regulates activity

0.946

In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM).

SIGNOR-263274

P52797

P54764

2

binding

up-regulates

0.826

Eph receptors are activated by their ligands, which are membrane-anchored molecules

SIGNOR-52315

Q02156

P18507

1

phosphorylation

down-regulates activity

0.233

Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.

SIGNOR-263174

P21728

P08754

2

binding

up-regulates activity

0.282

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-257181

Q99075

P08254

0

cleavage

up-regulates

0.517

It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor.

SIGNOR-83339

O00533

P16157

1

relocalization

up-regulates quantity

0.532

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266724

P04637

O75182

2

binding

down-regulates activity

0.497

The present study shows that under bleomycin-induced stress, expression of Sin3B gets up-regulated and it gets recruited by p53 at its target promoters. Knockdown of Sin3B leads to impaired negative regulation of p53 target genes and thus exemplifies Sin3B as a critical player in down-regulation of p53 subset target genes.

SIGNOR-266776

O15164

P10275

2

binding

up-regulates

0.396

We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar

SIGNOR-189113

Q92888

Q14344

2

binding

up-regulates activity

0.608

It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho

SIGNOR-256521

P10636

P49840

0

phosphorylation

down-regulates

0.429

Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.

SIGNOR-60651

P10588

Q05655

0

phosphorylation

down-regulates

0.2

Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.

SIGNOR-180017

Q13557

Q14571

1

phosphorylation

down-regulates activity

0.308

Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability.

SIGNOR-262692

P51452

P43405

0

phosphorylation

up-regulates activity

0.363

ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).

SIGNOR-275999

P50750

P35813

0

dephosphorylation

down-regulates activity

0.493

Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function

SIGNOR-248490

P48454

Q13469

1

dephosphorylation

up-regulates activity

0.408

NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity

SIGNOR-248512

P53350

Q99640

1

phosphorylation

down-regulates activity

0.721

Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site.

SIGNOR-263096

Q969Q6

P53041

2

binding

up-regulates activity

0.346

Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function

SIGNOR-272480

Q9NVW2

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.2

Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM.|Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter.

SIGNOR-268980

P04637

Q13362

0

dephosphorylation

up-regulates quantity by stabilization

0.611

Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation.

SIGNOR-268154

P54792

P05771

2

binding

up-regulates

0.2

Taken together, these results suggest that site-specific dvl2 phosphorylation is required for dvl2 association with pkc_. This interaction is likely to be one of the mechanisms essential for wnt3a-dependent neurite outgrowth.

SIGNOR-199457

Q9P2J3

Q96GD4

2

binding

up-regulates activity

0.71

Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis.

SIGNOR-271658

P00519

Q92918

1

phosphorylation

up-regulates activity

0.379

C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD

SIGNOR-251429

Q01082

Q8NG27

0

ubiquitination

down-regulates

0.403

The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it.

SIGNOR-141216

Q02952

P17612

2

relocalization

up-regulates activity

0.2

A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor.

SIGNOR-271835

Q96A00

O75116

0

phosphorylation

up-regulates activity

0.413

A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].

SIGNOR-96696

Q92838

Q9UNE0

2

binding

up-regulates

0.751

Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain.

SIGNOR-161109

P01116

P21359

2

binding

down-regulates activity

0.721

Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.

SIGNOR-273661

Q9NPH3

P01584

2

binding

up-regulates

0.867

The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri).

SIGNOR-61744

Q07869

P28702

2

binding

up-regulates

0.564

Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology

SIGNOR-105448

P25098

P30559

1

phosphorylation

down-regulates activity

0.2

Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization

SIGNOR-270329

Q8N157

P54257

2

binding

up-regulates activity

0.549

Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis.

SIGNOR-269081

P60484

P06239

0

phosphorylation

up-regulates

0.374

Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo.

SIGNOR-116499

P19174

O43561

2

binding

up-regulates activity

0.808

By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.

SIGNOR-246060

Q9Y4H4

P62873

2

binding

down-regulates quantity by destabilization

0.385

GPSM3 was found not only to modulate heterotrimeric G-protein subunit signaling through its two active GoLoco motifs, but also to affect monomeric Gbeta subunit biosynthesis and stability|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.

SIGNOR-264865

Q13049

Q86U86

1

ubiquitination

down-regulates quantity by destabilization

0.2

TRIM32 ubiquitination of PB1 leads to its protein degradation.

SIGNOR-278735

O60664

P20645

1

relocalization

up-regulates activity

0.73

TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.

SIGNOR-253093

Q00526

P18846

1

phosphorylation

up-regulates

0.2

Cyclin-dependent kinase 3-mediated activating transcription factor 1 phosphorylation enhances cell transformationwe found that cdk3 phosphorylates activating transcription factor 1 (atf1) at serine 63 and enhances the transactivation and transcriptional activities of atf1.

SIGNOR-180920

P30679

P28335

2

binding

up-regulates activity

0.503

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-257355

P41968

P01189

2

binding

up-regulates activity

0.759

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

SIGNOR-268705

P31751

O95988

2

binding

up-regulates

0.56

In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.

SIGNOR-81716

P36956

P54646

0

phosphorylation

down-regulates

0.328

Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372

SIGNOR-173031

O43521

Q16539

0

phosphorylation

down-regulates quantity by destabilization

0.32

Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination.

SIGNOR-260442

Q00535

Q9UKV5

1

phosphorylation

down-regulates quantity by destabilization

0.248

We found that GP78 expression is decreased in MPTP-based cellular and animal PD models, and CDK5 directly phosphorylated GP78 at Ser516, which promoted the ubiquitination and degradation of GP78.

SIGNOR-277356

P19838

Q9UKL3

2

binding

up-regulates

0.246

In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex.

SIGNOR-177104

Q96M98

P0DMV9

2

binding

up-regulates quantity by stabilization

0.2

Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo.

SIGNOR-272891

P63096

Q9GZQ6

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-256708

Q9H4B4

Q07817

1

phosphorylation

up-regulates

0.391

Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest.

SIGNOR-172230

O75385

Q7Z3C6

1

phosphorylation

up-regulates activity

0.582

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

SIGNOR-266369

Q9GZQ6

O15130

2

binding

up-regulates

0.747

Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems

SIGNOR-82916

P41221

P34925

2

binding

up-regulates

0.784

Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells.

SIGNOR-258970

P04637

Q9H2X6

0

phosphorylation

up-regulates

0.797

Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation.

SIGNOR-151930

P08575

P19784

0

phosphorylation

up-regulates activity

0.434

Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.

SIGNOR-251031

P53667

Q16566

0

phosphorylation

up-regulates activity

0.256

An active form of CaMKIV but not CaMKI enhanced Thr 508 phosphorylation of LIMK1 and increased the kinase activity of LIMK1.|Taken together, our results suggest that LIMK1 mediated cofilin phosphorylation is critical for ionomycin induced neurite outgrowth and that CaMKIV mediates ionomycin induced LIMK1 activation.

SIGNOR-280201

P06730

P67775

0

dephosphorylation

down-regulates

0.347

A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function.

SIGNOR-168306

P55347

P49639

2

binding

up-regulates activity

0.588

Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding.

SIGNOR-220242

Q13261

P43405

0

phosphorylation

up-regulates activity

0.329

Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells

SIGNOR-246556

Q13158

O14965

0

phosphorylation

up-regulates

0.343

Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194

SIGNOR-176739

Q6UY11

P46531

2

binding

down-regulates activity

0.29

Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.

SIGNOR-219377

Q96KG7

O95477

2

binding

up-regulates activity

0.332

ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.

SIGNOR-265165

P01138

P07996

2

binding

up-regulates

0.278

We have identified a mechanism for the activation of latent tgf-beta that involves binding of the secreted and extracellular matrix protein, thrombospondin-1 (tsp-1), to the latent precursor.

SIGNOR-75624

Q9Y2Z0

P53350

0

phosphorylation

up-regulates activity

0.437

Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone

SIGNOR-265222

Q6ZN44

P43146

2

binding

down-regulates activity

0.661

In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.

SIGNOR-268164

Q9H2X6

O00257

1

phosphorylation

up-regulates activity

0.423

In addition, HIPK2 phosphorylates Pc2 at several sites, including threonine 495.

SIGNOR-278484

Q9NR09

P42574

2

binding

down-regulates

0.464

Bruce binds and thereby inhibits caspases, in particular effector caspase-3.

SIGNOR-125956

P45985

O15264

1

phosphorylation

up-regulates activity

0.459

p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.

SIGNOR-273956

Q92837

P17612

0

phosphorylation

down-regulates

0.2

Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription.

SIGNOR-149689

P03372

O96013

0

phosphorylation

up-regulates activity

0.277

Further, PAK4 phosphorylated ER\u03b1-Ser305, a phosphorylation event needed for the PAK4 activation of ER\u03b1-dependent transcription.|Further, PAK4 phosphorylated ERalpha-Ser305, a phosphorylation event needed for the PAK4 activation of ERalpha dependent transcription.

SIGNOR-279472

Q13467

Q13145

2

binding

up-regulates

0.583

These data together suggest that bambi may form a ternary coreceptor complex with fzd5 and lrp6

SIGNOR-23040

Q9UQM7

Q12959

1

phosphorylation

down-regulates activity

0.649

Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII.

SIGNOR-250618

P07384

P55085

1

cleavage

down-regulates activity

0.298

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3

SIGNOR-263580

P51784

P68104

1

deubiquitination

up-regulates activity

0.2

USP11 interacted with and deubiquitinated eEF1A1 on Lys439, thereby inhibiting its ubiquitin-mediated degradation. Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription

SIGNOR-278107

P11161

O00308

0

ubiquitination

down-regulates quantity

0.372

The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination|AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death.

SIGNOR-268849

O75385

P19367

1

phosphorylation

up-regulates activity

0.257

Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).

SIGNOR-274033

O60674

Q9UQQ2

2

binding

down-regulates activity

0.643

we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions.

SIGNOR-260075

Q04206

P48729

0

phosphorylation

up-regulates activity

0.2

These data strongly suggested that CKI phosphorylated Ser-316 of p65. Our data suggested that phosphorylation of p65 on Ser-316 controls the activity and function of NF-κB. Importantly, we found that phosphorylation at the novel Ser-316 site and other two known phosphorylation sites, Ser-529 and Ser-536, either individually or cooperatively, regulated distinct groups of NF-κB-dependent genes, suggesting the unique role of each individual phosphorylation site on NF-κB-dependent gene regulation.

SIGNOR-276916

P35222

P22223

2

binding

up-regulates activity

0.851

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

SIGNOR-265865

Q9HC29

P0DMV8

2

binding

up-regulates quantity by stabilization

0.256

The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease.

SIGNOR-252416

Q6JBY9

P45983

0

phosphorylation

down-regulates activity

0.286

CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263085

Q96P68

P63092

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 ‚â• -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 ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256770

O15197

P29317

2

binding

down-regulates activity

0.422

EphB6 is frequently silenced in invasive and metastatic cancers; however, its role in cancer progression is poorly understood. Here we show that EphB6 interacts with EphA2 and suppresses EphA2-mediated promotion of anoikis resistance in MCF7 breast cancer cells.

SIGNOR-273853

Q9UQM7

P16949

1

phosphorylation

down-regulates

0.403

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.

SIGNOR-149640

Q14493

Q8N257

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265388

Q9BPV8

Q14344

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-257299

Q96PU5

Q9NY46

1

ubiquitination

down-regulates quantity by destabilization

0.283

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253464