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
Q9ULT6	O60353	1	ubiquitination	down-regulates quantity	0.614	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260114
P42262	Q5JU85	0	relocalization	up-regulates quantity	0.2	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264913
Q8IV63	P51452	2	binding	up-regulates activity	0.704	Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding	SIGNOR-275546
P55212	P49810	1	cleavage	up-regulates activity	0.363	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261750
P19447	P18074	2	binding	up-regulates	0.955	Xpd helps xpb in promoter opening and as such participates in the transcription reaction.	SIGNOR-64672
Q13158	O00220	2	binding	up-regulates	0.831	Fadd binds to ligated trailr1 or trail-r2	SIGNOR-97869
P07237	O75460	2	binding	down-regulates activity	0.427	The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity.	SIGNOR-275573
P01023	P14780	2	binding	down-regulates activity	0.492	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity\| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261801
Q14653	P35813	0	dephosphorylation	down-regulates activity	0.247	In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).\|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG).	SIGNOR-277152
Q07817	P24941	0	phosphorylation	up-regulates activity	0.496	Our findings show that Cdk2 phosphorylation of Bcl-xL at Ser73, but not the Bcl-xL cleavage products, is necessary and sufficient to induce cell death.	SIGNOR-278242
Q15831	Q8TDC3	1	phosphorylation	up-regulates	0.485	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122413
P45983	Q4V328	2	binding	up-regulates activity	0.311	To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons. GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1.	SIGNOR-260639
P10721	Q5JUK2	0	transcriptional regulation	up-regulates quantity by expression	0.346	Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.	SIGNOR-266205
P03206	Q92985	2	binding	down-regulates activity	0.2	We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters	SIGNOR-266643
Q8N431	P01112	2	binding	up-regulates	0.2	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-161505
O15169	P36894	1	ubiquitination	down-regulates	0.331	Other proteins, such as the serine/threonine kinase fused (fu), can function in concert with the e3 ligase smurf to regulate ubiquitination and proteolysis of the bmp receptor	SIGNOR-195552
P43220	P01275	2	binding	up-regulates	0.782	In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin	SIGNOR-34855
P35548	Q9UKT8	2	binding	down-regulates quantity by destabilization	0.2	Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase. Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation.	SIGNOR-272259
P03372	P31751	0	phosphorylation	up-regulates activity	0.509	AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT.	SIGNOR-251490
Q96G01	P49841	0	phosphorylation	up-regulates activity	0.331	Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein.	SIGNOR-262744
P06241	Q96J02	1	phosphorylation	down-regulates activity	0.366	Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation	SIGNOR-245332
P12830	Q96RU2	0	deubiquitination	up-regulates quantity by stabilization	0.2	Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage	SIGNOR-274057
Q5XUX0	P12830	2	binding	down-regulates quantity by destabilization	0.2	Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.	SIGNOR-277377
P20929	P49841	0	phosphorylation	down-regulates	0.306	Gsk3b is able to phosphorylate nebulin at two ser sites in the c-terminal region of nebulin localized to the z-disk, thus preventing the interaction of nebulin with neuronal wiscott-aldrich syndrome protein (nwasp), a ubiquitously expressed member of the wasp family, which is involved in actin assembly.	SIGNOR-175659
P51531	Q8TAQ2	2	binding	up-regulates	0.9	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65435
O43318	Q9NQC7	0	deubiquitination	up-regulates activity	0.636	Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades.	SIGNOR-266437
P48664	P35398	0	transcriptional regulation	up-regulates quantity by expression	0.251	RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice.	SIGNOR-266850
P42224	Q04206	2	binding	down-regulates	0.518	Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease.	SIGNOR-144561
O15379	P68400	0	phosphorylation	up-regulates activity	0.531	A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.	SIGNOR-250889
Q9UNE7	Q8IXT1	1	ubiquitination	down-regulates quantity by destabilization	0.322	HSP70 recruits DDIAS to the CHIP E3 ligase, whereas CHIP promotes the ubiquitination of DDIAS.\|However, the findings clearly demonstrated that HSP70 was solely involved in CHIP mediated proteasomal degradation of DDIAS.	SIGNOR-278784
P15056	P01116	2	binding	up-regulates activity	0.876	The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-156906
Q14774	P18146	1	transcriptional regulation	down-regulates quantity by repression	0.262	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261621
Q96FE5	Q9NQC3	2	binding	up-regulates	0.666	Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1,	SIGNOR-133752
P46734	Q16539	1	phosphorylation	up-regulates activity	0.728	Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.	SIGNOR-232156
Q9BVA0	O75449	2	binding	up-regulates quantity by stabilization	0.753	In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer	SIGNOR-267173
P52179	Q5VST9	1	relocalization	up-regulates quantity	0.3	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins.	SIGNOR-266727
P52735	O60716	2	binding	up-regulates	0.61	We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn	SIGNOR-198941
P45985	Q16584	0	phosphorylation	up-regulates	0.625	These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo.	SIGNOR-75836
P48730	Q00987	1	phosphorylation	down-regulates	0.345	Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase.	SIGNOR-167497
Q05655	P48995	1	phosphorylation	up-regulates activity	0.2	Taken together, these results indicate that store depletion induces interactions between TRPC1 and PKC\u03b4 in VSMCs, and that these interactions cause PKC\u03b4\u2010dependent phosphorylation of TRPC1.	SIGNOR-279559
P63104	P07196	2	binding	down-regulates activity	0.277	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252397
P36888	P46527	1	phosphorylation	down-regulates activity	0.29	FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia\|P27Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88.	SIGNOR-269208
P04629	Q13191	0	ubiquitination	down-regulates quantity	0.276	Cbl-b modulated TrkA ubiquitination and function in the dorsal root ganglion of mice.\|Viral expression of constitutively active Cbl-b in DRGs of osteoarthritic mice effectively repressed TrkA protein level and more importantly, alleviated mechanical allodynia and heat hyperalgesia.	SIGNOR-278690
Q9Y5I2	Q9Y5G2	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265710
P08238	Q9HC29	2	binding	up-regulates quantity by stabilization	0.321	Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation.	SIGNOR-252415
P28347	Q9GZV5	2	binding	up-regulates	0.868	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4.	SIGNOR-192768
Q9UI32	P23771	0	transcriptional regulation	up-regulates quantity by expression	0.332	Thus, GATA3 contributes to the elevated expression of GLS2 in luminal-subtype breast cancers.	SIGNOR-268034
Q9BXH1	Q92843	2	binding	down-regulates	0.552	Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133814
Q99835	P49407	2	binding	up-regulates	0.635	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-132678
P15056	Q96TA1	1	phosphorylation	down-regulates activity	0.2	Overall, this indicates that BRAF-dependent phosphorylation of FAM129B controls its cellular localization and thus its ability to bind to KEAP1 to block NRF2 degradation.	SIGNOR-279595
P67775	Q9NRL3	2	binding	up-regulates activity	0.571	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261697
P24941	Q6PKG0	1	phosphorylation	up-regulates activity	0.2	CDK2 phosphorylates LARP1 protein, regulates TOP-protein expression and LARP1\u2019s translational activity.	SIGNOR-279015
Q07954	P12931	0	phosphorylation	up-regulates activity	0.394	We recently observed that the ldl receptor-related protein 1 (lrp-1) is tyrosine phosphorylated in v-src-transformed cells.Of the four tyrosine residues present in the cytoplasmic domain of lrp-1, only tyr 63 is phosphorylated by v-src in vivo or in vitro. Using fibroblasts deficient in src, yes and fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate lrp-1. Tyrosine-phosphorylated lrp-1 associates with shc, a ptb and sh2 domain containing signaling protein that is involved in the activation of ras	SIGNOR-101535
P05106	Q99704	2	binding	down-regulates activity	0.334	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257687
Q13873	Q6KF10	2	binding	up-regulates	0.592	We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins.	SIGNOR-139093
P63027	Q9Y4I1	2	binding	up-regulates activity	0.484	Another potential role of myosin Va in LDCV exocytosis lies in facilitating the formation of the SNARE complex, which is needed for fusion of the vesicle with the plasma membrane. Notably, myosin Va binds to at least two SNARE proteins in a Ca2+-dependent manner: at micromolar Ca2+-levels, it binds to VAMP2 located in the membrane of the cargo vesicle via its globular tail domain	SIGNOR-269281
P45983	P30305	1	phosphorylation	down-regulates quantity by destabilization	0.284	Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276352
Q8TDD2	Q16539	0	phosphorylation	up-regulates activity	0.408	We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes	SIGNOR-255791
Q9Y5H9	O60330	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265676
P51671	P51677	2	binding	up-regulates	0.936	Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils	SIGNOR-254356
P60484	P19338	1	dephosphorylation	up-regulates activity	0.27	The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis.	SIGNOR-277166
Q15858	Q92913	2	binding	down-regulates activity	0.357	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253423
O95837	Q969F8	2	binding	up-regulates activity	0.435	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256893
P0DMV9	Q9UL15	2	binding	down-regulates activity	0.683	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.	SIGNOR-261197
P22681	Q04759	0	phosphorylation	up-regulates activity	0.355	PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins	SIGNOR-274144
Q92854	O43157	2	binding	up-regulates	0.808	Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors.	SIGNOR-92201
Q99418	P62330	1	guanine nucleotide exchange factor	up-regulates activity	0.887	Effects of ARNO upon Axonogenesis Are Mediated by Downstream Activation of ARF6. ARNO/ARF6 signaling pathways that could modulate actin reorganization in the axonal growth cone. ARNO stimulates GTP exchange on ARF6, thereby increasing the amount of active ARF6.	SIGNOR-264910
Q53EZ4	P28482	0	phosphorylation	down-regulates	0.367	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140890
Q96G91	P19086	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-257328
P67775	P12931	2	dephosphorylation	down-regulates activity	0.43	We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC	SIGNOR-247970
P11310	P37231	2	binding	down-regulates activity	0.346	This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation	SIGNOR-261264
P06493	Q969R2	1	phosphorylation	up-regulates activity	0.2	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.\|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264878
Q9NT62	Q9H492	2	binding	up-regulates	0.855	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe.	SIGNOR-191543
P67775	Q13188	1	dephosphorylation	down-regulates	0.693	Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.	SIGNOR-201266
Q15717	O96017	0	phosphorylation	down-regulates activity	0.55	Given the fact that Chk2 phosphorylates HuR at residues S88, S100 and T118 and that each individual phosphorylation site by Chk2 plays a distinct role in regulating HuR- binding to different target mRNAs (22,42), we further tested HuR mutants with alanine substitutions at each of the Chk2 phosphorylation sites.	SIGNOR-278163
Q12857	P54764	1	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268894
P05387	P25098	0	phosphorylation	up-regulates	0.2	The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity.	SIGNOR-94254
Q9UJM3	P12931	0	phosphorylation	down-regulates activity	0.414	Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.\|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395.	SIGNOR-279116
P17480	P06400	2	binding	down-regulates activity	0.376	Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product	SIGNOR-262589
Q13546	O15111	0	phosphorylation	down-regulates activity	0.54	Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.\|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb.	SIGNOR-278927
P68431	Q05655	0	phosphorylation	up-regulates activity	0.2	We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation.	SIGNOR-185144
Q8WUI4	Q9UPG8	1	deacetylation	down-regulates	0.258	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140953
Q8TBB1	Q96KB5	1	ubiquitination	down-regulates quantity by destabilization	0.375	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272898
P48061	P25106	2	binding	up-regulates	0.72	Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1.	SIGNOR-139709
Q15437	Q9Y6Y8	2	binding	up-regulates activity	0.347	The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.	SIGNOR-265306
P42229	P23470	0	dephosphorylation	up-regulates activity	0.265	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254730
P46934	O75843	2	monoubiquitination	up-regulates activity	0.401	Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.	SIGNOR-272634
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
Q9BUB5	P28482	0	phosphorylation	up-regulates	0.594	We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e).	SIGNOR-48298
P31749	Q9UQC2	1	phosphorylation	down-regulates	0.699	Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.	SIGNOR-252468
P37231	P11274	0	phosphorylation	down-regulates activity	0.2	Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).\|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82.	SIGNOR-279441
P00519	P35637	1	phosphorylation	down-regulates activity	0.325	Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS.	SIGNOR-280168
Q969H0	Q9UHV7	1	ubiquitination	down-regulates quantity by destabilization	0.371	The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.	SIGNOR-266690
P08912	P08754	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-256873
Q9P2S2	Q8NFZ3	2	binding	up-regulates activity	0.2	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264153
P34998	P06850	2	binding	up-regulates	0.958	Crf and ucn bind and activate crf-r1 with similarly high affinities.	SIGNOR-108713
P05549	P17612	0	phosphorylation	up-regulates	0.2	Recombinant ap-2 was phosphorylated in vitro by protein kinase a (pka) at ser239. Mutation of ser239 to ala abolished in vitro phosphorylation of ap-2 by pka, but not the dna binding activity of ap-2. Cotransfection studies showed that pka stimulated the effect of ap-2 on the apoe promoter, but not that of the s239a mutant.	SIGNOR-64955
Q07812	P21796	2	binding	up-regulates activity	0.584	The recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC	SIGNOR-249613
P49841	O15294	1	phosphorylation	up-regulates activity	0.518	But OGT activity is modulated by GSK3beta (XREF_FIG) and GSK3beta activity is known to oscillate through Ser9 phoshorylation.\|Here, we found that OGT is phosphorylated at serines 3 or 4 by GSK3beta and that O GlcNAcylation of OGT also occurs on the same or neighboring serine residues, suggesting interacting phosphorylation and O GlcNAcylation events on OGT itself.	SIGNOR-279528
P23588	P23443	0	phosphorylation	up-regulates	0.776	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123997

Q9ULT6

O60353

1

ubiquitination

down-regulates quantity

0.614

Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.

SIGNOR-260114

P42262

Q5JU85

0

relocalization

up-regulates quantity

0.2

BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.

SIGNOR-264913

Q8IV63

P51452

2

binding

up-regulates activity

0.704

Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding

SIGNOR-275546

P55212

P49810

1

cleavage

up-regulates activity

0.363

In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.

SIGNOR-261750

P19447

P18074

2

binding

up-regulates

0.955

Xpd helps xpb in promoter opening and as such participates in the transcription reaction.

SIGNOR-64672

Q13158

O00220

2

binding

up-regulates

0.831

Fadd binds to ligated trailr1 or trail-r2

SIGNOR-97869

P07237

O75460

2

binding

down-regulates activity

0.427

The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity.

SIGNOR-275573

P01023

P14780

2

binding

down-regulates activity

0.492

Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261801

Q14653

P35813

0

dephosphorylation

down-regulates activity

0.247

In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG).

SIGNOR-277152

Q07817

P24941

0

phosphorylation

up-regulates activity

0.496

Our findings show that Cdk2 phosphorylation of Bcl-xL at Ser73, but not the Bcl-xL cleavage products, is necessary and sufficient to induce cell death.

SIGNOR-278242

Q15831

Q8TDC3

1

phosphorylation

up-regulates

0.485

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122413

P45983

Q4V328

2

binding

up-regulates activity

0.311

To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons. GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1.

SIGNOR-260639

P10721

Q5JUK2

0

transcriptional regulation

up-regulates quantity by expression

0.346

Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.

SIGNOR-266205

P03206

Q92985

2

binding

down-regulates activity

0.2

We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters

SIGNOR-266643

Q8N431

P01112

2

binding

up-regulates

0.2

Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.

SIGNOR-161505

O15169

P36894

1

ubiquitination

down-regulates

0.331

Other proteins, such as the serine/threonine kinase fused (fu), can function in concert with the e3 ligase smurf to regulate ubiquitination and proteolysis of the bmp receptor

SIGNOR-195552

P43220

P01275

2

binding

up-regulates

0.782

In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin

SIGNOR-34855

P35548

Q9UKT8

2

binding

down-regulates quantity by destabilization

0.2

Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase. Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation.

SIGNOR-272259

P03372

P31751

0

phosphorylation

up-regulates activity

0.509

AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT.

SIGNOR-251490

Q96G01

P49841

0

phosphorylation

up-regulates activity

0.331

Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein.

SIGNOR-262744

P06241

Q96J02

1

phosphorylation

down-regulates activity

0.366

Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation

SIGNOR-245332

P12830

Q96RU2

0

deubiquitination

up-regulates quantity by stabilization

0.2

Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage

SIGNOR-274057

Q5XUX0

P12830

2

binding

down-regulates quantity by destabilization

0.2

Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.

SIGNOR-277377

P20929

P49841

0

phosphorylation

down-regulates

0.306

Gsk3b is able to phosphorylate nebulin at two ser sites in the c-terminal region of nebulin localized to the z-disk, thus preventing the interaction of nebulin with neuronal wiscott-aldrich syndrome protein (nwasp), a ubiquitously expressed member of the wasp family, which is involved in actin assembly.

SIGNOR-175659

P51531

Q8TAQ2

2

binding

up-regulates

0.9

The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.

SIGNOR-65435

O43318

Q9NQC7

0

deubiquitination

up-regulates activity

0.636

Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades.

SIGNOR-266437

P48664

P35398

0

transcriptional regulation

up-regulates quantity by expression

0.251

RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice.

SIGNOR-266850

P42224

Q04206

2

binding

down-regulates

0.518

Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease.

SIGNOR-144561

O15379

P68400

0

phosphorylation

up-regulates activity

0.531

A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.

SIGNOR-250889

Q9UNE7

Q8IXT1

1

ubiquitination

down-regulates quantity by destabilization

0.322

HSP70 recruits DDIAS to the CHIP E3 ligase, whereas CHIP promotes the ubiquitination of DDIAS.|However, the findings clearly demonstrated that HSP70 was solely involved in CHIP mediated proteasomal degradation of DDIAS.

SIGNOR-278784

P15056

P01116

2

binding

up-regulates activity

0.876

The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.

SIGNOR-156906

Q14774

P18146

1

transcriptional regulation

down-regulates quantity by repression

0.262

In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.

SIGNOR-261621

Q96FE5

Q9NQC3

2

binding

up-regulates

0.666

Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1,

SIGNOR-133752

P46734

Q16539

1

phosphorylation

up-regulates activity

0.728

Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.

SIGNOR-232156

Q9BVA0

O75449

2

binding

up-regulates quantity by stabilization

0.753

In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer

SIGNOR-267173

P52179

Q5VST9

1

relocalization

up-regulates quantity

0.3

Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins.

SIGNOR-266727

P52735

O60716

2

binding

up-regulates

0.61

We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn

SIGNOR-198941

P45985

Q16584

0

phosphorylation

up-regulates

0.625

These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo.

SIGNOR-75836

P48730

Q00987

1

phosphorylation

down-regulates

0.345

Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase.

SIGNOR-167497

Q05655

P48995

1

phosphorylation

up-regulates activity

0.2

Taken together, these results indicate that store depletion induces interactions between TRPC1 and PKC\u03b4 in VSMCs, and that these interactions cause PKC\u03b4\u2010dependent phosphorylation of TRPC1.

SIGNOR-279559

P63104

P07196

2

binding

down-regulates activity

0.277

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

SIGNOR-252397

P36888

P46527

1

phosphorylation

down-regulates activity

0.29

FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia|P27Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88.

SIGNOR-269208

P04629

Q13191

0

ubiquitination

down-regulates quantity

0.276

Cbl-b modulated TrkA ubiquitination and function in the dorsal root ganglion of mice.|Viral expression of constitutively active Cbl-b in DRGs of osteoarthritic mice effectively repressed TrkA protein level and more importantly, alleviated mechanical allodynia and heat hyperalgesia.

SIGNOR-278690

Q9Y5I2

Q9Y5G2

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265710

P08238

Q9HC29

2

binding

up-regulates quantity by stabilization

0.321

Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation.

SIGNOR-252415

P28347

Q9GZV5

2

binding

up-regulates

0.868

When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4.

SIGNOR-192768

Q9UI32

P23771

0

transcriptional regulation

up-regulates quantity by expression

0.332

Thus, GATA3 contributes to the elevated expression of GLS2 in luminal-subtype breast cancers.

SIGNOR-268034

Q9BXH1

Q92843

2

binding

down-regulates

0.552

Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.

SIGNOR-133814

Q99835

P49407

2

binding

up-regulates

0.635

Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2

SIGNOR-132678

P15056

Q96TA1

1

phosphorylation

down-regulates activity

0.2

Overall, this indicates that BRAF-dependent phosphorylation of FAM129B controls its cellular localization and thus its ability to bind to KEAP1 to block NRF2 degradation.

SIGNOR-279595

P67775

Q9NRL3

2

binding

up-regulates activity

0.571

The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms

SIGNOR-261697

P24941

Q6PKG0

1

phosphorylation

up-regulates activity

0.2

CDK2 phosphorylates LARP1 protein, regulates TOP-protein expression and LARP1\u2019s translational activity.

SIGNOR-279015

Q07954

P12931

0

phosphorylation

up-regulates activity

0.394

We recently observed that the ldl receptor-related protein 1 (lrp-1) is tyrosine phosphorylated in v-src-transformed cells.Of the four tyrosine residues present in the cytoplasmic domain of lrp-1, only tyr 63 is phosphorylated by v-src in vivo or in vitro. Using fibroblasts deficient in src, yes and fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate lrp-1. Tyrosine-phosphorylated lrp-1 associates with shc, a ptb and sh2 domain containing signaling protein that is involved in the activation of ras

SIGNOR-101535

P05106

Q99704

2

binding

down-regulates activity

0.334

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257687

Q13873

Q6KF10

2

binding

up-regulates

0.592

We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins.

SIGNOR-139093

P63027

Q9Y4I1

2

binding

up-regulates activity

0.484

Another potential role of myosin Va in LDCV exocytosis lies in facilitating the formation of the SNARE complex, which is needed for fusion of the vesicle with the plasma membrane. Notably, myosin Va binds to at least two SNARE proteins in a Ca2+-dependent manner: at micromolar Ca2+-levels, it binds to VAMP2 located in the membrane of the cargo vesicle via its globular tail domain

SIGNOR-269281

P45983

P30305

1

phosphorylation

down-regulates quantity by destabilization

0.284

Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).

SIGNOR-276352

Q8TDD2

Q16539

0

phosphorylation

up-regulates activity

0.408

We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes

SIGNOR-255791

Q9Y5H9

O60330

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265676

P51671

P51677

2

binding

up-regulates

0.936

Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils

SIGNOR-254356

P60484

P19338

1

dephosphorylation

up-regulates activity

0.27

The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis.

SIGNOR-277166

Q15858

Q92913

2

binding

down-regulates activity

0.357

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253423

O95837

Q969F8

2

binding

up-regulates activity

0.435

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256893

P0DMV9

Q9UL15

2

binding

down-regulates activity

0.683

Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.

SIGNOR-261197

P22681

Q04759

0

phosphorylation

up-regulates activity

0.355

PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins

SIGNOR-274144

Q92854

O43157

2

binding

up-regulates

0.808

Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors.

SIGNOR-92201

Q99418

P62330

1

guanine nucleotide exchange factor

up-regulates activity

0.887

Effects of ARNO upon Axonogenesis Are Mediated by Downstream Activation of ARF6. ARNO/ARF6 signaling pathways that could modulate actin reorganization in the axonal growth cone. ARNO stimulates GTP exchange on ARF6, thereby increasing the amount of active ARF6.

SIGNOR-264910

Q53EZ4

P28482

0

phosphorylation

down-regulates

0.367

Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.

SIGNOR-140890

Q96G91

P19086

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-257328

P67775

P12931

2

dephosphorylation

down-regulates activity

0.43

We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC

SIGNOR-247970

P11310

P37231

2

binding

down-regulates activity

0.346

This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation

SIGNOR-261264

P06493

Q969R2

1

phosphorylation

up-regulates activity

0.2

CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.

SIGNOR-264878

Q9NT62

Q9H492

2

binding

up-regulates

0.855

Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe.

SIGNOR-191543

P67775

Q13188

1

dephosphorylation

down-regulates

0.693

Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.

SIGNOR-201266

Q15717

O96017

0

phosphorylation

down-regulates activity

0.55

Given the fact that Chk2 phosphorylates HuR at residues S88, S100 and T118 and that each individual phosphorylation site by Chk2 plays a distinct role in regulating HuR- binding to different target mRNAs (22,42), we further tested HuR mutants with alanine substitutions at each of the Chk2 phosphorylation sites.

SIGNOR-278163

Q12857

P54764

1

transcriptional regulation

up-regulates quantity

0.2

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

SIGNOR-268894

P05387

P25098

0

phosphorylation

up-regulates

0.2

The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity.

SIGNOR-94254

Q9UJM3

P12931

0

phosphorylation

down-regulates activity

0.414

Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395.

SIGNOR-279116

P17480

P06400

2

binding

down-regulates activity

0.376

Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product

SIGNOR-262589

Q13546

O15111

0

phosphorylation

down-regulates activity

0.54

Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb.

SIGNOR-278927

P68431

Q05655

0

phosphorylation

up-regulates activity

0.2

We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation.

SIGNOR-185144

Q8WUI4

Q9UPG8

1

deacetylation

down-regulates

0.258

Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.

SIGNOR-140953

Q8TBB1

Q96KB5

1

ubiquitination

down-regulates quantity by destabilization

0.375

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.

SIGNOR-272898

P48061

P25106

2

binding

up-regulates

0.72

Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1.

SIGNOR-139709

Q15437

Q9Y6Y8

2

binding

up-regulates activity

0.347

The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.

SIGNOR-265306

P42229

P23470

0

dephosphorylation

up-regulates activity

0.265

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

SIGNOR-254730

P46934

O75843

2

monoubiquitination

up-regulates activity

0.401

Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.

SIGNOR-272634

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

Q9BUB5

P28482

0

phosphorylation

up-regulates

0.594

We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e).

SIGNOR-48298

P31749

Q9UQC2

1

phosphorylation

down-regulates

0.699

Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.

SIGNOR-252468

P37231

P11274

0

phosphorylation

down-regulates activity

0.2

Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82.

SIGNOR-279441

P00519

P35637

1

phosphorylation

down-regulates activity

0.325

Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS.

SIGNOR-280168

Q969H0

Q9UHV7

1

ubiquitination

down-regulates quantity by destabilization

0.371

The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.

SIGNOR-266690

P08912

P08754

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-256873

Q9P2S2

Q8NFZ3

2

binding

up-regulates activity

0.2

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264153

P34998

P06850

2

binding

up-regulates

0.958

Crf and ucn bind and activate crf-r1 with similarly high affinities.

SIGNOR-108713

P05549

P17612

0

phosphorylation

up-regulates

0.2

Recombinant ap-2 was phosphorylated in vitro by protein kinase a (pka) at ser239. Mutation of ser239 to ala abolished in vitro phosphorylation of ap-2 by pka, but not the dna binding activity of ap-2. Cotransfection studies showed that pka stimulated the effect of ap-2 on the apoe promoter, but not that of the s239a mutant.

SIGNOR-64955

Q07812

P21796

2

binding

up-regulates activity

0.584

The recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC

SIGNOR-249613

P49841

O15294

1

phosphorylation

up-regulates activity

0.518

But OGT activity is modulated by GSK3beta (XREF_FIG) and GSK3beta activity is known to oscillate through Ser9 phoshorylation.|Here, we found that OGT is phosphorylated at serines 3 or 4 by GSK3beta and that O GlcNAcylation of OGT also occurs on the same or neighboring serine residues, suggesting interacting phosphorylation and O GlcNAcylation events on OGT itself.

SIGNOR-279528

P23588

P23443

0

phosphorylation

up-regulates

0.776

S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.

SIGNOR-123997