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
P68363	Q5SQI0	0	acetylation	up-regulates quantity by stabilization	0.252	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272245
P49841	Q02156	2	phosphorylation	up-regulates	0.268	Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368)	SIGNOR-179412
Q02156	P29353	1	phosphorylation	up-regulates activity	0.2	Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.	SIGNOR-263048
Q13625	Q96A00	2	binding	down-regulates	0.2	The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations.	SIGNOR-39666
P10276	P50613	0	phosphorylation	up-regulates	0.546	However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant.	SIGNOR-49693
P04629	P12931	0	phosphorylation	up-regulates activity	0.292	Direct phosphorylation of TrkA by Src family kinases has been demonstrated in vitro, and our studies suggest that Src may lead to selective activation of TrkA.	SIGNOR-279291
P10415	Q15173	0	dephosphorylation	down-regulates	0.323	Pp2a directly interacts with the bh4 domain of bcl2 as a docking site to potentially bridge pp2a to bcl2's flexible loop domain containing the target serine 70 phosphorylation site.	SIGNOR-181559
P04637	P62714	0	dephosphorylation	up-regulates quantity by stabilization	0.437	A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55\| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis	SIGNOR-248583
P0CG48	P09936	0	cleavage	up-regulates quantity	0.864	These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains	SIGNOR-249693
P34969	P38405	2	binding	up-regulates activity	0.444	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-256926
P21860	Q01973	0	phosphorylation	up-regulates activity	0.343	Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation.\|ROR1 knockdown decreased phosphorylations of ERBB3, c-Src, and AKT in NKX2-1 + / ROR1 + NCI-H1975, SK-LC-5, and NCI-H358 cells.	SIGNOR-279279
Q8TD19	Q8TD19	2	phosphorylation	up-regulates	0.2	We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif.	SIGNOR-173026
P12931	P06396	1	phosphorylation	up-regulates	0.572	Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently	SIGNOR-67014
Q16778	Q68DK7	0	monoubiquitination	down-regulates activity	0.2	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271977
P67775	O43524	1	dephosphorylation	up-regulates	0.402	Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-163680
Q13148	O14920	0	phosphorylation	down-regulates quantity by destabilization	0.2	IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK.	SIGNOR-277860
Q9UBK2	Q13131	0	phosphorylation	up-regulates activity	0.575	Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538.	SIGNOR-156780
Q15796	Q9H4A3	0	phosphorylation	up-regulates quantity	0.2	In addition, WNK1 and WNK4 can phosphorylate Smad2, and silencing of WNK1 reduces Smad2 protein levels in HeLa cells, suggesting that WNKs have complex effects on TGFbeta signaling, which itself can promote cancer or act in a tumor suppressing manner.	SIGNOR-280164
P41240	P06239	1	phosphorylation	down-regulates	0.538	P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity.	SIGNOR-20371
P17252	Q9NQA5	1	phosphorylation	up-regulates activity	0.2	A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK.	SIGNOR-149948
P19876	P25025	2	binding	up-regulates activity	0.723	CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively	SIGNOR-277719
O60664	P11717	1	relocalization	up-regulates activity	0.725	TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.	SIGNOR-253092
P53350	P60484	1	phosphorylation	down-regulates activity	0.534	Subsequently, Plk1 phosphorylation of PTEN was shown to be responsible for its inactivation.	SIGNOR-280070
P60880	P46459	2	binding	down-regulates activity	0.722	NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers	SIGNOR-263974
P18031	P19235	1	dephosphorylation	down-regulates activity	0.459	In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.\|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling.	SIGNOR-276994
P37231	Q13547	1	relocalization	down-regulates	0.617	These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome	SIGNOR-143961
Q7Z7A1	O15078	2	binding	down-regulates activity	0.47	CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state	SIGNOR-252149
Q96GD4	Q8WWK9	1	phosphorylation	up-regulates	0.296	Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap.	SIGNOR-165410
O95476	Q14693	1	dephosphorylation	up-regulates activity	0.78	Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.\|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol	SIGNOR-248346
P06241	P29353	1	phosphorylation	up-regulates	0.732	Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.	SIGNOR-59623
O95271	Q13148	2	binding	up-regulates quantity by stabilization	0.2	Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation.	SIGNOR-262115
Q96RI0	Q14344	2	binding	up-regulates	0.408	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)	SIGNOR-196015
Q9Y618	P24941	0	phosphorylation	down-regulates activity	0.429	Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.\|Cdk2 phosphorylates SMRT at consensus Cdk motifs to generate Pin1 binding sites and consequently targets SMRT for degradation, the latter also requiring the PPIase activity of Pin1 (XREF_FIG).	SIGNOR-278306
P32929	Q13237	0	phosphorylation	down-regulates activity	0.244	CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) of CSE, inhibiting the production of H2S.	SIGNOR-275800
Q86WV6	O75385	0	phosphorylation	down-regulates activity	0.2	Collectively, our data indicates that cGAS is essential for the activation of AMPK and ULK1 suppression of STING (XREF_FIG) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity (XREF_FIG).\|Collectively, our data indicates that cGAS is essential for the activation of AMPK/ULK1 suppression of STING ( xref ) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity ( xref ).	SIGNOR-279316
Q14186	Q01094	2	binding	up-regulates activity	0.815	DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle.	SIGNOR-253865
Q86Y13	P0C0S5	1	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271748
Q16828	P45983	1	dephosphorylation	down-regulates activity	0.632	Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.\|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells.	SIGNOR-277150
P48729	O00257	1	phosphorylation	down-regulates quantity by destabilization	0.2	The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.	SIGNOR-277512
Q9NUW8	Q13315	0	phosphorylation	up-regulates	0.542	Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)	SIGNOR-188772
O60729	Q16659	1	dephosphorylation	down-regulates quantity by destabilization	0.571	Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.\|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248336
P63279	P05412	1	sumoylation	down-regulates activity	0.42	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.\|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity.	SIGNOR-263001
Q9GZQ8	Q9Y4P1	0	cleavage	up-regulates	0.803	Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.	SIGNOR-125449
P34998	P63096	2	binding	up-regulates activity	0.453	Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3	SIGNOR-268618
P27986	Q02763	2	binding	up-regulates activity	0.538	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242634
P22681	Q8IZP0	2	binding	up-regulates	0.371	Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf.	SIGNOR-154162
Q8TF42	P22681	2	binding	down-regulates	0.443	Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways.	SIGNOR-124897
Q96RI0	P63096	2	binding	up-regulates	0.385	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)	SIGNOR-151162
Q01974	P21333	2	binding	up-regulates	0.439	Additionally, the association of ror2 with the actin-binding protein filamin a is required for wnt5a-induced jnk activation and polarized cell migration.	SIGNOR-179668
Q9H3D4	P00519	0	phosphorylation	up-regulates quantity by stabilization	0.543	In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters.	SIGNOR-260934
Q04721	P49841	0	phosphorylation	down-regulates activity	0.481	We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093.	SIGNOR-101570
Q8IW35	Q9H3F6	2	binding	down-regulates quantity by destabilization	0.2	Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. we identified the cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole.	SIGNOR-272923
P23458	Q13261	0	null	up-regulates	0.462	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256227
P45983	Q13387	2	binding	up-regulates	0.638	These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.	SIGNOR-70860
P68400	Q92769	1	phosphorylation	up-regulates	0.619	Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation.	SIGNOR-164795
Q9UBU9	O94901	2	binding	up-regulates activity	0.354	SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1.	SIGNOR-263296
P23760	P49841	0	phosphorylation	up-regulates quantity	0.334	The ubiquitously expressed CK2 often provides the priming phosphorylation for GSK-3, however, we found that GSK-3beta alone was sufficient to phosphorylate PAX3 at both Ser205 and Ser197 and Ser201 in-vitro.	SIGNOR-278482
Q5VWQ8	O60674	2	binding	down-regulates activity	0.349	In vascular smooth muscle cells (VSMCs) treated with IFN-γ, DAB2IP directly binds to JAK2 and inhibits its kinase activity, limiting JAK-dependent STAT1/3 and PI3K–AKT phosphorylation and activation	SIGNOR-254760
Q92974	O14965	0	phosphorylation	down-regulates activity	0.332	The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity.	SIGNOR-276061
P00367	Q9Y6E7	0	glycosylation	down-regulates activity	0.62	We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity.	SIGNOR-267828
P47900	Q03113	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-257394
P10275	Q13043	0	phosphorylation	down-regulates activity	0.2	Here we showed that MST1 is an androgen receptor kinase and phosphorylates androgen receptor at Ser-650 ( ).\|Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter.	SIGNOR-280143
Q12778	Q14680	0	phosphorylation	down-regulates quantity	0.257	Direct phosphorylation of FOXO1 and FOXO3 by MELK.\|Our findings revealed that siRNA mediated MELK knockdown increased protein levels of FOXO1 and FOXO3, which might increase p21 transcriptional level in a p53 independent manner.	SIGNOR-279543
Q9UBI6	P43115	2	binding	up-regulates	0.45	Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)	SIGNOR-88195
P07948	P25490	1	phosphorylation	down-regulates activity	0.2	In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B).	SIGNOR-276930
Q9Y4D1	P12931	0	phosphorylation	up-regulates activity	0.325	Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.\|PTPN3 suppresses lung cancer cell invasiveness by counteracting Src mediated DAAM1 activation and actin polymerization.	SIGNOR-280128
Q9Y616	Q9NWZ3	2	binding	down-regulates	0.713	Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation	SIGNOR-205434
P04792	P23443	0	phosphorylation	down-regulates	0.309	Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk.	SIGNOR-186959
Q9P2G9	Q13702	2	binding	down-regulates quantity by destabilization	0.482	We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn.	SIGNOR-271781
Q15418	P49427	1	phosphorylation	down-regulates quantity by destabilization	0.335	RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation.	SIGNOR-277330
P52306	P62745	2	binding	up-regulates	0.279	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171615
O96017	Q13315	0	phosphorylation	up-regulates activity	0.835	Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir	SIGNOR-81403
Q93074	P10071	2	binding	down-regulates	0.504	We propose that activated gli3 physically targets med12 in mediator to reverse mediator-dependent suppression of shh target gene (i.e., Gli1 or cyclin d1) transcription.	SIGNOR-149876
Q96MT8	Q96SN8	0	relocalization	up-regulates activity	0.692	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271722
P08754	P11229	2	binding	up-regulates activity	0.343	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-256878
Q92813	P60604	0	ubiquitination	down-regulates quantity by destabilization	0.2	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-267484
O94811	P28482	0	phosphorylation	down-regulates activity	0.354	Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262928
P28482	O94811	1	phosphorylation	down-regulates activity	0.354	Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262928
P21912	Q9NX18	2	binding	up-regulates	0.617	Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity	SIGNOR-187239
P17252	P17302	1	phosphorylation	down-regulates	0.535	Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.	SIGNOR-120907
P62714	P31751	1	dephosphorylation	down-regulates	0.481	These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity	SIGNOR-42123
Q96CN9	Q15811	1	relocalization	up-regulates activity	0.2	GFP-GCC88 was immunoprecipitated by both the short and long form of ITSN-1 but not with FLAG-Rheb (Figure 4A). These data demonstrate that both GCC88 and ITSN-1 are part of a complex. We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).	SIGNOR-260600
O14974	O95835	0	phosphorylation	up-regulates activity	0.47	LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1.\|This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity.	SIGNOR-278184
O14904	Q9NPG1	2	binding	up-regulates	0.622	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-132070
Q05397	P62993	2	binding	up-regulates activity	0.706	Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade.	SIGNOR-257733
P00533	O15492	1	phosphorylation	up-regulates	0.415	Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells.	SIGNOR-98267
P01137	P63151	2	binding	up-regulates activity	0.385	The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217894
P49840	Q9BYG3	1	phosphorylation	up-regulates activity	0.2	The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.	SIGNOR-262697
P04626	P00519	1	phosphorylation	up-regulates activity	0.373	In this study, we show that Abl kinase SH2 domains bind directly to Her-2, and like PDGFR-beta, Her-2 directly phosphorylates c-Abl.	SIGNOR-279407
P58401	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-264158
P25090	P49913	2	binding	up-regulates	0.533	Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1.	SIGNOR-82701
O14713	P26010	2	binding	down-regulates activity	0.287	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-257664
Q05655	Q16206	1	phosphorylation	up-regulates	0.2	Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein.	SIGNOR-197706
Q9GZU7	Q15796	1	dephosphorylation	down-regulates activity	0.515	SCP1 Dephosphorylates Smad2/3 in the Linkers\|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248795
Q99698	P20339	2	binding	down-regulates activity	0.266	Mauve interacts with Rab5, Msps, and gamma-tubulin\|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment	SIGNOR-266001
Q08881	Q96LC7	1	phosphorylation	up-regulates	0.2	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112471
Q99250	P49841	0	phosphorylation	down-regulates activity	0.2	Glycogen synthase kinase 3β (GSK3beta) phosphorylates the Nav1.2C-terminal tail at T1966, suppressing Na+ currents and channel trafficking to the plasma membrane	SIGNOR-275748
O96017	Q9HC98	1	phosphorylation	down-regulates activity	0.229	Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro .	SIGNOR-279404
Q06187	Q06187	2	phosphorylation	up-regulates	0.2	Overexpression of btk with a src family kinase increases tyrosine phosphorylation and catalytic activity of btk. This occurs by transphosphorylation at y551 in the btk catalytic domain and the enhancement of btk autophosphorylation at a second site. We mapped the major btk autophosphorylation site to y223 within the sh3 domain	SIGNOR-41480
P52292	Q14653	1	relocalization	up-regulates activity	0.2	The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F).	SIGNOR-262514

P68363

Q5SQI0

0

acetylation

up-regulates quantity by stabilization

0.252

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272245

P49841

Q02156

2

phosphorylation

up-regulates

0.268

Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368)

SIGNOR-179412

Q02156

P29353

1

phosphorylation

up-regulates activity

0.2

Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.

SIGNOR-263048

Q13625

Q96A00

2

binding

down-regulates

0.2

The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations.

SIGNOR-39666

P10276

P50613

0

phosphorylation

up-regulates

0.546

However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant.

SIGNOR-49693

P04629

P12931

0

phosphorylation

up-regulates activity

0.292

Direct phosphorylation of TrkA by Src family kinases has been demonstrated in vitro, and our studies suggest that Src may lead to selective activation of TrkA.

SIGNOR-279291

P10415

Q15173

0

dephosphorylation

down-regulates

0.323

Pp2a directly interacts with the bh4 domain of bcl2 as a docking site to potentially bridge pp2a to bcl2's flexible loop domain containing the target serine 70 phosphorylation site.

SIGNOR-181559

P04637

P62714

0

dephosphorylation

up-regulates quantity by stabilization

0.437

A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis

SIGNOR-248583

P0CG48

P09936

0

cleavage

up-regulates quantity

0.864

These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains

SIGNOR-249693

P34969

P38405

2

binding

up-regulates activity

0.444

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-256926

P21860

Q01973

0

phosphorylation

up-regulates activity

0.343

Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation.|ROR1 knockdown decreased phosphorylations of ERBB3, c-Src, and AKT in NKX2-1 + / ROR1 + NCI-H1975, SK-LC-5, and NCI-H358 cells.

SIGNOR-279279

Q8TD19

2

phosphorylation

up-regulates

0.2

We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif.

SIGNOR-173026

P12931

P06396

1

phosphorylation

up-regulates

0.572

Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently

SIGNOR-67014

Q16778

Q68DK7

0

monoubiquitination

down-regulates activity

0.2

MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.

SIGNOR-271977

P67775

O43524

1

dephosphorylation

up-regulates

0.402

Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.

SIGNOR-163680

Q13148

O14920

0

phosphorylation

down-regulates quantity by destabilization

0.2

IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK.

SIGNOR-277860

Q9UBK2

Q13131

0

phosphorylation

up-regulates activity

0.575

Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538.

SIGNOR-156780

Q15796

Q9H4A3

0

phosphorylation

up-regulates quantity

0.2

In addition, WNK1 and WNK4 can phosphorylate Smad2, and silencing of WNK1 reduces Smad2 protein levels in HeLa cells, suggesting that WNKs have complex effects on TGFbeta signaling, which itself can promote cancer or act in a tumor suppressing manner.

SIGNOR-280164

P41240

P06239

1

phosphorylation

down-regulates

0.538

P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity.

SIGNOR-20371

P17252

Q9NQA5

1

phosphorylation

up-regulates activity

0.2

A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK.

SIGNOR-149948

P19876

P25025

2

binding

up-regulates activity

0.723

CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively

SIGNOR-277719

O60664

P11717

1

relocalization

up-regulates activity

0.725

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

SIGNOR-253092

P53350

P60484

1

phosphorylation

down-regulates activity

0.534

Subsequently, Plk1 phosphorylation of PTEN was shown to be responsible for its inactivation.

SIGNOR-280070

P60880

P46459

2

binding

down-regulates activity

0.722

NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers

SIGNOR-263974

P18031

P19235

1

dephosphorylation

down-regulates activity

0.459

In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling.

SIGNOR-276994

P37231

Q13547

1

relocalization

down-regulates

0.617

These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome

SIGNOR-143961

Q7Z7A1

O15078

2

binding

down-regulates activity

0.47

CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state

SIGNOR-252149

Q96GD4

Q8WWK9

1

phosphorylation

up-regulates

0.296

Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap.

SIGNOR-165410

O95476

Q14693

1

dephosphorylation

up-regulates activity

0.78

Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol

SIGNOR-248346

P06241

P29353

1

phosphorylation

up-regulates

0.732

Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.

SIGNOR-59623

O95271

Q13148

2

binding

up-regulates quantity by stabilization

0.2

Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation.

SIGNOR-262115

Q96RI0

Q14344

2

binding

up-regulates

0.408

Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)

SIGNOR-196015

Q9Y618

P24941

0

phosphorylation

down-regulates activity

0.429

Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.|Cdk2 phosphorylates SMRT at consensus Cdk motifs to generate Pin1 binding sites and consequently targets SMRT for degradation, the latter also requiring the PPIase activity of Pin1 (XREF_FIG).

SIGNOR-278306

P32929

Q13237

0

phosphorylation

down-regulates activity

0.244

CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) of CSE, inhibiting the production of H2S.

SIGNOR-275800

Q86WV6

O75385

0

phosphorylation

down-regulates activity

0.2

Collectively, our data indicates that cGAS is essential for the activation of AMPK and ULK1 suppression of STING (XREF_FIG) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity (XREF_FIG).|Collectively, our data indicates that cGAS is essential for the activation of AMPK/ULK1 suppression of STING ( xref ) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity ( xref ).

SIGNOR-279316

Q14186

Q01094

2

binding

up-regulates activity

0.815

DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle.

SIGNOR-253865

Q86Y13

P0C0S5

1

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271748

Q16828

P45983

1

dephosphorylation

down-regulates activity

0.632

Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells.

SIGNOR-277150

P48729

O00257

1

phosphorylation

down-regulates quantity by destabilization

0.2

The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.

SIGNOR-277512

Q9NUW8

Q13315

0

phosphorylation

up-regulates

0.542

Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)

SIGNOR-188772

O60729

Q16659

1

dephosphorylation

down-regulates quantity by destabilization

0.571

Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.

SIGNOR-248336

P63279

P05412

1

sumoylation

down-regulates activity

0.42

We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity.

SIGNOR-263001

Q9GZQ8

Q9Y4P1

0

cleavage

up-regulates

0.803

Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.

SIGNOR-125449

P34998

P63096

2

binding

up-regulates activity

0.453

Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3

SIGNOR-268618

P27986

Q02763

2

binding

up-regulates activity

0.538

Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival

SIGNOR-242634

P22681

Q8IZP0

2

binding

up-regulates

0.371

Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf.

SIGNOR-154162

Q8TF42

P22681

2

binding

down-regulates

0.443

Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways.

SIGNOR-124897

Q96RI0

P63096

2

binding

up-regulates

0.385

Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)

SIGNOR-151162

Q01974

P21333

2

binding

up-regulates

0.439

Additionally, the association of ror2 with the actin-binding protein filamin a is required for wnt5a-induced jnk activation and polarized cell migration.

SIGNOR-179668

Q9H3D4

P00519

0

phosphorylation

up-regulates quantity by stabilization

0.543

In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters.

SIGNOR-260934

Q04721

P49841

0

phosphorylation

down-regulates activity

0.481

We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093.

SIGNOR-101570

Q8IW35

Q9H3F6

2

binding

down-regulates quantity by destabilization

0.2

Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. we identified the cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole.

SIGNOR-272923

P23458

Q13261

0

null

up-regulates

0.462

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256227

P45983

Q13387

2

binding

up-regulates

0.638

These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.

SIGNOR-70860

P68400

Q92769

1

phosphorylation

up-regulates

0.619

Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation.

SIGNOR-164795

Q9UBU9

O94901

2

binding

up-regulates activity

0.354

SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1.

SIGNOR-263296

P23760

P49841

0

phosphorylation

up-regulates quantity

0.334

The ubiquitously expressed CK2 often provides the priming phosphorylation for GSK-3, however, we found that GSK-3beta alone was sufficient to phosphorylate PAX3 at both Ser205 and Ser197 and Ser201 in-vitro.

SIGNOR-278482

Q5VWQ8

O60674

2

binding

down-regulates activity

0.349

In vascular smooth muscle cells (VSMCs) treated with IFN-γ, DAB2IP directly binds to JAK2 and inhibits its kinase activity, limiting JAK-dependent STAT1/3 and PI3K–AKT phosphorylation and activation

SIGNOR-254760

Q92974

O14965

0

phosphorylation

down-regulates activity

0.332

The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity.

SIGNOR-276061

P00367

Q9Y6E7

0

glycosylation

down-regulates activity

0.62

We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity.

SIGNOR-267828

P47900

Q03113

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-257394

P10275

Q13043

0

phosphorylation

down-regulates activity

0.2

Here we showed that MST1 is an androgen receptor kinase and phosphorylates androgen receptor at Ser-650 ( ).|Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter.

SIGNOR-280143

Q12778

Q14680

0

phosphorylation

down-regulates quantity

0.257

Direct phosphorylation of FOXO1 and FOXO3 by MELK.|Our findings revealed that siRNA mediated MELK knockdown increased protein levels of FOXO1 and FOXO3, which might increase p21 transcriptional level in a p53 independent manner.

SIGNOR-279543

Q9UBI6

P43115

2

binding

up-regulates

0.45

Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)

SIGNOR-88195

P07948

P25490

1

phosphorylation

down-regulates activity

0.2

In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B).

SIGNOR-276930

Q9Y4D1

P12931

0

phosphorylation

up-regulates activity

0.325

Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.|PTPN3 suppresses lung cancer cell invasiveness by counteracting Src mediated DAAM1 activation and actin polymerization.

SIGNOR-280128

Q9Y616

Q9NWZ3

2

binding

down-regulates

0.713

Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation

SIGNOR-205434

P04792

P23443

0

phosphorylation

down-regulates

0.309

Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk.

SIGNOR-186959

Q9P2G9

Q13702

2

binding

down-regulates quantity by destabilization

0.482

We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn.

SIGNOR-271781

Q15418

P49427

1

phosphorylation

down-regulates quantity by destabilization

0.335

RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation.

SIGNOR-277330

P52306

P62745

2

binding

up-regulates

0.279

Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob

SIGNOR-171615

O96017

Q13315

0

phosphorylation

up-regulates activity

0.835

Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir

SIGNOR-81403

Q93074

P10071

2

binding

down-regulates

0.504

We propose that activated gli3 physically targets med12 in mediator to reverse mediator-dependent suppression of shh target gene (i.e., Gli1 or cyclin d1) transcription.

SIGNOR-149876

Q96MT8

Q96SN8

0

relocalization

up-regulates activity

0.692

Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.

SIGNOR-271722

P08754

P11229

2

binding

up-regulates activity

0.343

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-256878

Q92813

P60604

0

ubiquitination

down-regulates quantity by destabilization

0.2

ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.

SIGNOR-267484

O94811

P28482

0

phosphorylation

down-regulates activity

0.354

Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.

SIGNOR-262928

P28482

O94811

1

phosphorylation

down-regulates activity

0.354

Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.

SIGNOR-262928

P21912

Q9NX18

2

binding

up-regulates

0.617

Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity

SIGNOR-187239

P17252

P17302

1

phosphorylation

down-regulates

0.535

Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.

SIGNOR-120907

P62714

P31751

1

dephosphorylation

down-regulates

0.481

These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity

SIGNOR-42123

Q96CN9

Q15811

1

relocalization

up-regulates activity

0.2

GFP-GCC88 was immunoprecipitated by both the short and long form of ITSN-1 but not with FLAG-Rheb (Figure 4A). These data demonstrate that both GCC88 and ITSN-1 are part of a complex. We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).

SIGNOR-260600

O14974

O95835

0

phosphorylation

up-regulates activity

0.47

LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1.|This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity.

SIGNOR-278184

O14904

Q9NPG1

2

binding

up-regulates

0.622

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-132070

Q05397

P62993

2

binding

up-regulates activity

0.706

Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade.

SIGNOR-257733

P00533

O15492

1

phosphorylation

up-regulates

0.415

Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells.

SIGNOR-98267

P01137

P63151

2

binding

up-regulates activity

0.385

The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity

SIGNOR-217894

P49840

Q9BYG3

1

phosphorylation

up-regulates activity

0.2

The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.

SIGNOR-262697

P04626

P00519

1

phosphorylation

up-regulates activity

0.373

In this study, we show that Abl kinase SH2 domains bind directly to Her-2, and like PDGFR-beta, Her-2 directly phosphorylates c-Abl.

SIGNOR-279407

P58401

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-264158

P25090

P49913

2

binding

up-regulates

0.533

Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1.

SIGNOR-82701

O14713

P26010

2

binding

down-regulates activity

0.287

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-257664

Q05655

Q16206

1

phosphorylation

up-regulates

0.2

Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein.

SIGNOR-197706

Q9GZU7

Q15796

1

dephosphorylation

down-regulates activity

0.515

SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity

SIGNOR-248795

Q99698

P20339

2

binding

down-regulates activity

0.266

Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment

SIGNOR-266001

Q08881

Q96LC7

1

phosphorylation

up-regulates

0.2

These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling

SIGNOR-112471

Q99250

P49841

0

phosphorylation

down-regulates activity

0.2

Glycogen synthase kinase 3β (GSK3beta) phosphorylates the Nav1.2C-terminal tail at T1966, suppressing Na+ currents and channel trafficking to the plasma membrane

SIGNOR-275748

O96017

Q9HC98

1

phosphorylation

down-regulates activity

0.229

Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro .

SIGNOR-279404

Q06187

2

phosphorylation

up-regulates

0.2

Overexpression of btk with a src family kinase increases tyrosine phosphorylation and catalytic activity of btk. This occurs by transphosphorylation at y551 in the btk catalytic domain and the enhancement of btk autophosphorylation at a second site. We mapped the major btk autophosphorylation site to y223 within the sh3 domain

SIGNOR-41480

P52292

Q14653

1

relocalization

up-regulates activity

0.2

The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F).

SIGNOR-262514