GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
Q13459	P60953	1	gtpase-activating protein	down-regulates activity	0.562	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260511
Q14703	P36956	1	cleavage	up-regulates activity	0.561	We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2	SIGNOR-267497
Q14703	Q70SY1	1	cleavage	up-regulates	0.561	Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei	SIGNOR-151309
Q9UM11	O14965	1	binding	down-regulates quantity by destabilization	0.561	We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.	SIGNOR-272610
Q13627	P37840	1	phosphorylation	up-regulates	0.561	In vitro kinase assay of anti-dyrk1a immunocomplexes demonstrated that dyrk1a could phosphorylate alpha-synuclein at ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by dyrk1a, potentially affecting neuronal cell viability.	SIGNOR-149393
P24941	P06748	1	phosphorylation	down-regulates activity	0.561	Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.	SIGNOR-89609
O14578	P24844	1	phosphorylation	up-regulates activity	0.561	Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)\|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation.	SIGNOR-260306
O60271	Q16539	1	binding	up-regulates activity	0.561	Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants.	SIGNOR-149979
O95166	Q9NQX3	1	binding	up-regulates activity	0.561	The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms.	SIGNOR-264971
Q6PHR2	P10071	1	phosphorylation	up-regulates activity	0.561	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro	SIGNOR-260799
P35658	Q13485	1	binding	up-regulates	0.561	We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import	SIGNOR-117647
P06241	P14923	1	phosphorylation	up-regulates activity	0.561	Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity	SIGNOR-251176
Q13164	P51812	1	phosphorylation	up-regulates activity	0.561	This suggested that ERK5 may directly activate RSKs.\|In vitro active ERK5 also phosphorylated RSK2 that had been immunoprecipitated from transfected cells using an anti-HA antibody ( Fig. 2 B).\|Phosphorylation of RSK2 by ERK5 in vitro increased its activity towards GST-S6 as much as 8-fold (Figs. 2 C and E).	SIGNOR-279216
P27361	P06401	1	phosphorylation	down-regulates	0.561	Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.	SIGNOR-74716
P28300	O95967	1	binding	up-regulates activity	0.561	Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking.	SIGNOR-252135
P06241	P42768	1	phosphorylation	up-regulates activity	0.561	As shown in XREF_FIG F, Fyn immunoprecipitates from activated T cells induced the tyrosine phosphorylation of WASp, but neither WASpDeltaPro nor WASpY291F mutant proteins were phosphorylated in this assay.	SIGNOR-279333
Q15637	P35637	1	binding	down-regulates	0.561	We speculate that zfm1 may inhibit transcription driven by the ntds of tls	SIGNOR-58967
P61073	P63096	1	binding	up-regulates activity	0.561	Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner	SIGNOR-278102
Q13464	P19105	1	phosphorylation	up-regulates activity	0.561	Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies.	SIGNOR-263074
Q8N2W9	P42224	1	binding	down-regulates	0.561	First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1.	SIGNOR-105723
P24588	P17612	1	relocalization	up-regulates activity	0.561	In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150	SIGNOR-261292
Q9BQS8	Q9H492	1	binding	up-regulates activity	0.561	The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.	SIGNOR-260598
P16473	P50148	1	binding	up-regulates activity	0.561	Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations	SIGNOR-267138
P49841	Q13469	1	phosphorylation	down-regulates	0.561	Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat.	SIGNOR-179784
O95714	P38398	1	ubiquitination	down-regulates quantity by destabilization	0.561	HERC2 ubiquitinates BRCA1; this reaction depends on Cys(4762) of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1.\|Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G(2)-M checkpoint activity.	SIGNOR-278813
P28482	Q9NYA1	1	phosphorylation	up-regulates	0.561	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118546
Q14012	P17600	1	phosphorylation	down-regulates activity	0.561	Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I	SIGNOR-250615
O95988	P31751	1	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
Q14865	O75151	2	binding	up-regulates activity	0.56	We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.	SIGNOR-264515
Q9HCE7	Q13873	1	ubiquitination	down-regulates	0.56	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-153402
P31751	Q00987	1	phosphorylation	up-regulates quantity by stabilization	0.56	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-109732
Q15466	O75469	1	binding	down-regulates	0.56	Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments.	SIGNOR-101924
O75151	Q14865	2	binding	up-regulates activity	0.56	We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.	SIGNOR-264514
Q9UBD9	P40189	1	binding	up-regulates	0.56	Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-6	SIGNOR-47959
P17676	P16220-1	1	binding	up-regulates activity	0.56	We conclude that C/EBP-β can directly bind to the N-terminal Q1 domain of CREB in addition to binding to the leucine zipper domain. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-β enhanced the effect, while a dominant negative C/EBP inhibited it	SIGNOR-263654
P33176	Q9NX95	1	relocalization	up-regulates activity	0.56	Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.	SIGNOR-264811
O43474	P04637	1	transcriptional regulation	down-regulates quantity by repression	0.56	Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element.	SIGNOR-270544
Q9H469	Q9HCE7-2	1	binding	down-regulates quantity by destabilization	0.56	Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation. FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells.	SIGNOR-271909
P06239	P09693	1	phosphorylation	up-regulates activity	0.56	Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259931
Q6VVB1	P35573	1	ubiquitination	down-regulates quantity by destabilization	0.56	The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL.	SIGNOR-271669
P27361	P10415	1	phosphorylation	up-regulates	0.56	Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association.	SIGNOR-74935
Q9HBH9	P06730	1	phosphorylation	up-regulates	0.56	Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes.	SIGNOR-157537
Q9Y5W5	Q9H1J5	1	binding	down-regulates	0.56	Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities.	SIGNOR-66892
Q9UNH5	P30305	1	dephosphorylation	down-regulates activity	0.56	Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).\|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity.	SIGNOR-276968
Q7Z6B7	P63000	1	gtpase-activating protein	down-regulates activity	0.56	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260515
Q9GZT5	O75581	1	binding	up-regulates	0.56	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-131622
P10909	P98164	1	binding	up-regulates quantity	0.56	Our results demonstrate that circulating ApoJ is retained in muscle via LRP2 and that LRP2 signaling could play a role in the maintenance of ApoJ homeostasis in circulation, at least in part.	SIGNOR-265256
Q969P5	P15172	1	ubiquitination	down-regulates quantity by destabilization	0.56	Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy.	SIGNOR-184861
Q8IU57	P29597	1	binding	up-regulates	0.559	Despite signaling through distinct receptor complexes, type i ifns and ifn-_s activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (fig. 6). In both cases, receptor engagement leads via the activation of the jak kinases jak1 and tyk2	SIGNOR-124483
O14965	P49841	2	phosphorylation	down-regulates activity	0.559	The recombinant human AURKA protein phosphorylated the GSK-3beta protein at Ser 9 in a concentration-dependent manner, in vitro.	SIGNOR-279357
P41279	P45985	1	phosphorylation	up-regulates	0.559	Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1)	SIGNOR-196744
P41279	Q99558	1	phosphorylation	up-regulates activity	0.559	In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha	SIGNOR-249387
Q14596	Q9H492	1	binding	up-regulates	0.559	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family.	SIGNOR-184270
P12931	Q13224	1	phosphorylation	up-regulates activity	0.559	We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases	SIGNOR-247180
P31749	P14598	1	phosphorylation	up-regulates	0.559	Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.	SIGNOR-252586
P49841	O14965	2	phosphorylation	down-regulates activity	0.559	However, phosphorylation of AurA by GSK3B on S283/4 is known to promote autophosphorylation on S342 that is inhibitory to AurA activity, making it likely that GSK3B can govern AurA stability indirectly through conformational effects.\|In this study, GSK3B was proposed to promote FBXW7 targeting of AurA through priming a phospho-degron located in the kinase domain.	SIGNOR-279718
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
P31749	Q04912	1	phosphorylation	up-regulates	0.559	Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing	SIGNOR-252471
P09874	P04637	1	relocalization	up-regulates activity	0.559	We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.\|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus.	SIGNOR-261321
Q9Y4K3	P49768	1	ubiquitination	up-regulates quantity by stabilization	0.559	We have also observed that ubiquitination of PS1 by TRAF6 increases the stability of PS1 holoprotein, and TRAF6-deficiency coincides with reduced endogenous PS1 and PS2 levels.	SIGNOR-278601
P12931	P42224	1	phosphorylation	up-regulates activity	0.559	The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation.	SIGNOR-235696
Q99759	P46734	1	phosphorylation	up-regulates activity	0.558	These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3.	SIGNOR-48625
O15297	P04637	1	dephosphorylation	down-regulates activity	0.558	PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.	SIGNOR-248319
P53355	P04637	1	phosphorylation	up-regulates	0.558	Dna damage-activated protein kinases like chk1/2 modify the box-i domain of p53 at thr18 and ser20 (46) by an allosteric mechanism (10).	SIGNOR-153491
Q9UQ26	Q96E17	1	relocalization	up-regulates activity	0.558	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264378
Q5VT25	Q9BZL4	1	phosphorylation	down-regulates activity	0.558	Identification of the Phosphorylation Site of p85 on Threonine 560 by MRCKα-CAT \| Wild-type p85 but not the mutant p85AA, when phosphorylated in vitro with MRCKα-CAT, showed significant reduction in the rate of MLC2 dephosphorylation. These results confirm a similar observation with MBS130 where phosphorylation of a conserved threonine 695 within a highly conserved motif was essential for the inhibition of phosphatase catalytic activity	SIGNOR-250724
Q9HBE5	P52333	1	binding	up-regulates	0.558	Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5	SIGNOR-90269
Q13424	P29475	1	relocalization	up-regulates	0.558	biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein	SIGNOR-236916
Q15256	Q16539	1	dephosphorylation	down-regulates	0.558	As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl.	SIGNOR-111762
P29350	P35222	1	dephosphorylation	down-regulates quantity by destabilization	0.558	Because SHP-1 can dephosphorylate residues Y86 and Y654 on the \u03b2-catenin protein, these residues were therefore mutated into phenylalanine and the transcriptional activity of the subsequent \u03b2-catenin mutants analyzed: \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F. As shown in Fig.\u00a03 B, the mutants \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F had a significantly reduced transcriptional activity in comparison to wild-type \u03b2-catenin.\|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein.	SIGNOR-277014
P17252	P04049	1	phosphorylation	down-regulates	0.558	Pka can inhibit raf-1 function directly via phosphorylation of the raf-1 kinase domain	SIGNOR-34761
O95819	Q13233	1	phosphorylation	up-regulates	0.558	Hpk1 binds and phosphorylates mekk1 directly	SIGNOR-44040
Q05397	O43707	1	phosphorylation	down-regulates	0.558	Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin	SIGNOR-192195
P31749	P67809	1	phosphorylation	up-regulates	0.558	Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102	SIGNOR-252521
P49841	P12830	1	phosphorylation	up-regulates activity	0.558	Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849.	SIGNOR-251225
Q9Y4H2	P48736	1	binding	up-regulates	0.558	There was a high level of irs-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust pi3k binding and activation	SIGNOR-103174
Q6GPH4	P98170	1	binding	down-regulates	0.558	Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3.	SIGNOR-155637
Q03113	P61586	1	binding	up-regulates	0.558	Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.	SIGNOR-192108
P14784	P29353	1	binding	up-regulates	0.558	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204975
P31749	P41279	1	phosphorylation	up-regulates activity	0.558	Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.	SIGNOR-252572
P84550	P52954	1	binding	down-regulates activity	0.558	Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord.	SIGNOR-238004
Q13315	Q92630	1	phosphorylation	up-regulates quantity by stabilization	0.558	ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage\|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus.	SIGNOR-275577
P06239	P16885	1	phosphorylation	up-regulates	0.558	In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme.	SIGNOR-91477
Q8N2W9	Q13485	1	binding	down-regulates	0.558	Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity.	SIGNOR-104541
P61244	P50539	1	binding	up-regulates activity	0.558	The role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240314
P49841	O95863	1	phosphorylation	down-regulates	0.557	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129402
P14416	P08754	1	binding	up-regulates activity	0.557	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-256844
P49841	Q00613	1	phosphorylation	down-regulates activity	0.557	Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1.	SIGNOR-251216
P07948	Q05655	1	phosphorylation	down-regulates activity	0.557	Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro	SIGNOR-251407
P27361	P00533	1	phosphorylation	down-regulates	0.557	It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation.	SIGNOR-20549
P12931	P50570	1	phosphorylation	down-regulates activity	0.557	We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G).	SIGNOR-277539
P51451	P16885	1	phosphorylation	up-regulates activity	0.557	Lyn, Syk, Btk, and Blk can also phosphorylate and enhance the activation of phospholipase C gamma 2 (PLCgamma2), which hydrolyzes PI (4,5) P2 to create inositol 3,4,5-trisphosphate (IP3) and diacylglycerol (DAG), stimulating Ca 2+ mobilization and protein kinase C (PKC), respectively.	SIGNOR-280195
Q96AP0	O14746	1	binding	up-regulates	0.557	We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.	SIGNOR-152321
P31751	P49840	1	phosphorylation	down-regulates	0.557	Activated pi3k/akt pathway results in inhibitory phosphorylation of gsk3	SIGNOR-138179
P25101	Q14344	1	binding	up-regulates	0.557	We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain.	SIGNOR-66856
Q9Y2X7	P19174	1	binding	up-regulates	0.557	Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation	SIGNOR-118454
P08581	Q96S59	1	binding	up-regulates	0.557	Our data suggest that ranbpm, functioning as an adaptor protein for the met tyrosine kinase domain, can augment the hgf-met signaling pathway.	SIGNOR-91028
O14965	Q8NHV4	1	phosphorylation	up-regulates activity	0.557	Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A\| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone.	SIGNOR-272965
Q8WYK2	P15336	1	binding	down-regulates activity	0.557	JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE).	SIGNOR-226395
O95967	P15502	1	binding	up-regulates activity	0.557	Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking.	SIGNOR-252136

Q13459

P60953

1

gtpase-activating protein

down-regulates activity

0.562

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260511

Q14703

P36956

1

cleavage

up-regulates activity

0.561

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

SIGNOR-267497

Q14703

Q70SY1

1

cleavage

up-regulates

0.561

Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei

SIGNOR-151309

Q9UM11

O14965

1

binding

down-regulates quantity by destabilization

0.561

We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.

SIGNOR-272610

Q13627

P37840

1

phosphorylation

up-regulates

0.561

In vitro kinase assay of anti-dyrk1a immunocomplexes demonstrated that dyrk1a could phosphorylate alpha-synuclein at ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by dyrk1a, potentially affecting neuronal cell viability.

SIGNOR-149393

P24941

P06748

1

phosphorylation

down-regulates activity

0.561

Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.

SIGNOR-89609

O14578

P24844

1

phosphorylation

up-regulates activity

0.561

Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation.

SIGNOR-260306

O60271

Q16539

1

binding

up-regulates activity

0.561

Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants.

SIGNOR-149979

O95166

Q9NQX3

1

binding

up-regulates activity

0.561

The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms.

SIGNOR-264971

Q6PHR2

P10071

1

phosphorylation

up-regulates activity

0.561

We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro

SIGNOR-260799

P35658

Q13485

1

binding

up-regulates

0.561

We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import

SIGNOR-117647

P06241

P14923

1

phosphorylation

up-regulates activity

0.561

Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity

SIGNOR-251176

Q13164

P51812

1

phosphorylation

up-regulates activity

0.561

This suggested that ERK5 may directly activate RSKs.|In vitro active ERK5 also phosphorylated RSK2 that had been immunoprecipitated from transfected cells using an anti-HA antibody ( Fig. 2 B).|Phosphorylation of RSK2 by ERK5 in vitro increased its activity towards GST-S6 as much as 8-fold (Figs. 2 C and E).

SIGNOR-279216

P27361

P06401

1

phosphorylation

down-regulates

0.561

Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.

SIGNOR-74716

P28300

O95967

1

binding

up-regulates activity

0.561

Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking.

SIGNOR-252135

P06241

P42768

1

phosphorylation

up-regulates activity

0.561

As shown in XREF_FIG F, Fyn immunoprecipitates from activated T cells induced the tyrosine phosphorylation of WASp, but neither WASpDeltaPro nor WASpY291F mutant proteins were phosphorylated in this assay.

SIGNOR-279333

Q15637

P35637

1

binding

down-regulates

0.561

We speculate that zfm1 may inhibit transcription driven by the ntds of tls

SIGNOR-58967

P61073

P63096

1

binding

up-regulates activity

0.561

Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner

SIGNOR-278102

Q13464

P19105

1

phosphorylation

up-regulates activity

0.561

Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies.

SIGNOR-263074

Q8N2W9

P42224

1

binding

down-regulates

0.561

First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1.

SIGNOR-105723

P24588

P17612

1

relocalization

up-regulates activity

0.561

In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150

SIGNOR-261292

Q9BQS8

Q9H492

1

binding

up-regulates activity

0.561

The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.

SIGNOR-260598

P16473

P50148

1

binding

up-regulates activity

0.561

Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations

SIGNOR-267138

P49841

Q13469

1

phosphorylation

down-regulates

0.561

Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat.

SIGNOR-179784

O95714

P38398

1

ubiquitination

down-regulates quantity by destabilization

0.561

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

SIGNOR-278813

P28482

Q9NYA1

1

phosphorylation

up-regulates

0.561

Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.

SIGNOR-118546

Q14012

P17600

1

phosphorylation

down-regulates activity

0.561

Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I

SIGNOR-250615

O95988

P31751

1

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

Q14865

O75151

2

binding

up-regulates activity

0.56

We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.

SIGNOR-264515

Q9HCE7

Q13873

1

ubiquitination

down-regulates

0.56

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

SIGNOR-153402

P31751

Q00987

1

phosphorylation

up-regulates quantity by stabilization

0.56

Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.

SIGNOR-109732

Q15466

O75469

1

binding

down-regulates

0.56

Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments.

SIGNOR-101924

O75151

Q14865

2

binding

up-regulates activity

0.56

We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.

SIGNOR-264514

Q9UBD9

P40189

1

binding

up-regulates

0.56

Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-6

SIGNOR-47959

P17676

P16220-1

1

binding

up-regulates activity

0.56

We conclude that C/EBP-β can directly bind to the N-terminal Q1 domain of CREB in addition to binding to the leucine zipper domain. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-β enhanced the effect, while a dominant negative C/EBP inhibited it

SIGNOR-263654

P33176

Q9NX95

1

relocalization

up-regulates activity

0.56

Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.

SIGNOR-264811

O43474

P04637

1

transcriptional regulation

down-regulates quantity by repression

0.56

Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element.

SIGNOR-270544

Q9H469

Q9HCE7-2

1

binding

down-regulates quantity by destabilization

0.56

Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation. FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells.

SIGNOR-271909

P06239

P09693

1

phosphorylation

up-regulates activity

0.56

Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.

SIGNOR-259931

Q6VVB1

P35573

1

ubiquitination

down-regulates quantity by destabilization

0.56

The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL.

SIGNOR-271669

P27361

P10415

1

phosphorylation

up-regulates

0.56

Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association.

SIGNOR-74935

Q9HBH9

P06730

1

phosphorylation

up-regulates

0.56

Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes.

SIGNOR-157537

Q9Y5W5

Q9H1J5

1

binding

down-regulates

0.56

Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities.

SIGNOR-66892

Q9UNH5

P30305

1

dephosphorylation

down-regulates activity

0.56

Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity.

SIGNOR-276968

Q7Z6B7

P63000

1

gtpase-activating protein

down-regulates activity

0.56

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260515

Q9GZT5

O75581

1

binding

up-regulates

0.56

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-131622

P10909

P98164

1

binding

up-regulates quantity

0.56

Our results demonstrate that circulating ApoJ is retained in muscle via LRP2 and that LRP2 signaling could play a role in the maintenance of ApoJ homeostasis in circulation, at least in part.

SIGNOR-265256

Q969P5

P15172

1

ubiquitination

down-regulates quantity by destabilization

0.56

Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy.

SIGNOR-184861

Q8IU57

P29597

1

binding

up-regulates

0.559

Despite signaling through distinct receptor complexes, type i ifns and ifn-_s activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (fig. 6). In both cases, receptor engagement leads via the activation of the jak kinases jak1 and tyk2

SIGNOR-124483

O14965

P49841

2

phosphorylation

down-regulates activity

0.559

The recombinant human AURKA protein phosphorylated the GSK-3beta protein at Ser 9 in a concentration-dependent manner, in vitro.

SIGNOR-279357

P41279

P45985

1

phosphorylation

up-regulates

0.559

Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1)

SIGNOR-196744

P41279

Q99558

1

phosphorylation

up-regulates activity

0.559

In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha

SIGNOR-249387

Q14596

Q9H492

1

binding

up-regulates

0.559

We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family.

SIGNOR-184270

P12931

Q13224

1

phosphorylation

up-regulates activity

0.559

We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases

SIGNOR-247180

P31749

P14598

1

phosphorylation

up-regulates

0.559

Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.

SIGNOR-252586

P49841

O14965

2

phosphorylation

down-regulates activity

0.559

However, phosphorylation of AurA by GSK3B on S283/4 is known to promote autophosphorylation on S342 that is inhibitory to AurA activity, making it likely that GSK3B can govern AurA stability indirectly through conformational effects.|In this study, GSK3B was proposed to promote FBXW7 targeting of AurA through priming a phospho-degron located in the kinase domain.

SIGNOR-279718

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

P31749

Q04912

1

phosphorylation

up-regulates

0.559

Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing

SIGNOR-252471

P09874

P04637

1

relocalization

up-regulates activity

0.559

We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus.

SIGNOR-261321

Q9Y4K3

P49768

1

ubiquitination

up-regulates quantity by stabilization

0.559

We have also observed that ubiquitination of PS1 by TRAF6 increases the stability of PS1 holoprotein, and TRAF6-deficiency coincides with reduced endogenous PS1 and PS2 levels.

SIGNOR-278601

P12931

P42224

1

phosphorylation

up-regulates activity

0.559

The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation.

SIGNOR-235696

Q99759

P46734

1

phosphorylation

up-regulates activity

0.558

These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3.

SIGNOR-48625

O15297

P04637

1

dephosphorylation

down-regulates activity

0.558

PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.

SIGNOR-248319

P53355

P04637

1

phosphorylation

up-regulates

0.558

Dna damage-activated protein kinases like chk1/2 modify the box-i domain of p53 at thr18 and ser20 (46) by an allosteric mechanism (10).

SIGNOR-153491

Q9UQ26

Q96E17

1

relocalization

up-regulates activity

0.558

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

SIGNOR-264378

Q5VT25

Q9BZL4

1

phosphorylation

down-regulates activity

0.558

Identification of the Phosphorylation Site of p85 on Threonine 560 by MRCKα-CAT | Wild-type p85 but not the mutant p85AA, when phosphorylated in vitro with MRCKα-CAT, showed significant reduction in the rate of MLC2 dephosphorylation. These results confirm a similar observation with MBS130 where phosphorylation of a conserved threonine 695 within a highly conserved motif was essential for the inhibition of phosphatase catalytic activity

SIGNOR-250724

Q9HBE5

P52333

1

binding

up-regulates

0.558

Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5

SIGNOR-90269

Q13424

P29475

1

relocalization

up-regulates

0.558

biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein

SIGNOR-236916

Q15256

Q16539

1

dephosphorylation

down-regulates

0.558

As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl.

SIGNOR-111762

P29350

P35222

1

dephosphorylation

down-regulates quantity by destabilization

0.558

Because SHP-1 can dephosphorylate residues Y86 and Y654 on the \u03b2-catenin protein, these residues were therefore mutated into phenylalanine and the transcriptional activity of the subsequent \u03b2-catenin mutants analyzed: \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F. As shown in Fig.\u00a03 B, the mutants \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F had a significantly reduced transcriptional activity in comparison to wild-type \u03b2-catenin.|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein.

SIGNOR-277014

P17252

P04049

1

phosphorylation

down-regulates

0.558

Pka can inhibit raf-1 function directly via phosphorylation of the raf-1 kinase domain

SIGNOR-34761

O95819

Q13233

1

phosphorylation

up-regulates

0.558

Hpk1 binds and phosphorylates mekk1 directly

SIGNOR-44040

Q05397

O43707

1

phosphorylation

down-regulates

0.558

Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin

SIGNOR-192195

P31749

P67809

1

phosphorylation

up-regulates

0.558

Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102

SIGNOR-252521

P49841

P12830

1

phosphorylation

up-regulates activity

0.558

Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849.

SIGNOR-251225

Q9Y4H2

P48736

1

binding

up-regulates

0.558

There was a high level of irs-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust pi3k binding and activation

SIGNOR-103174

Q6GPH4

P98170

1

binding

down-regulates

0.558

Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3.

SIGNOR-155637

Q03113

P61586

1

binding

up-regulates

0.558

Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.

SIGNOR-192108

P14784

P29353

1

binding

up-regulates

0.558

The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival

SIGNOR-204975

P31749

P41279

1

phosphorylation

up-regulates activity

0.558

Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.

SIGNOR-252572

P84550

P52954

1

binding

down-regulates activity

0.558

Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord.

SIGNOR-238004

Q13315

Q92630

1

phosphorylation

up-regulates quantity by stabilization

0.558

ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus.

SIGNOR-275577

P06239

P16885

1

phosphorylation

up-regulates

0.558

In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme.

SIGNOR-91477

Q8N2W9

Q13485

1

binding

down-regulates

0.558

Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity.

SIGNOR-104541

P61244

P50539

1

binding

up-regulates activity

0.558

The role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.

SIGNOR-240314

P49841

O95863

1

phosphorylation

down-regulates

0.557

Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt

SIGNOR-129402

P14416

P08754

1

binding

up-regulates activity

0.557

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-256844

P49841

Q00613

1

phosphorylation

down-regulates activity

0.557

Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1.

SIGNOR-251216

P07948

Q05655

1

phosphorylation

down-regulates activity

0.557

Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro

SIGNOR-251407

P27361

P00533

1

phosphorylation

down-regulates

0.557

It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation.

SIGNOR-20549

P12931

P50570

1

phosphorylation

down-regulates activity

0.557

We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G).

SIGNOR-277539

P51451

P16885

1

phosphorylation

up-regulates activity

0.557

Lyn, Syk, Btk, and Blk can also phosphorylate and enhance the activation of phospholipase C gamma 2 (PLCgamma2), which hydrolyzes PI (4,5) P2 to create inositol 3,4,5-trisphosphate (IP3) and diacylglycerol (DAG), stimulating Ca 2+ mobilization and protein kinase C (PKC), respectively.

SIGNOR-280195

Q96AP0

O14746

1

binding

up-regulates

0.557

We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.

SIGNOR-152321

P31751

P49840

1

phosphorylation

down-regulates

0.557

Activated pi3k/akt pathway results in inhibitory phosphorylation of gsk3

SIGNOR-138179

P25101

Q14344

1

binding

up-regulates

0.557

We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain.

SIGNOR-66856

Q9Y2X7

P19174

1

binding

up-regulates

0.557

Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation

SIGNOR-118454

P08581

Q96S59

1

binding

up-regulates

0.557

Our data suggest that ranbpm, functioning as an adaptor protein for the met tyrosine kinase domain, can augment the hgf-met signaling pathway.

SIGNOR-91028

O14965

Q8NHV4

1

phosphorylation

up-regulates activity

0.557

Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone.

SIGNOR-272965

Q8WYK2

P15336

1

binding

down-regulates activity

0.557

JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE).

SIGNOR-226395

O95967

P15502

1

binding

up-regulates activity

0.557

Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking.

SIGNOR-252136