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
P10747	P06239	0	phosphorylation	up-regulates	0.754	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-45524
Q9Y5K5	Q15796	1	deubiquitination	up-regulates	0.378	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases	SIGNOR-138876
P61925	P00533	0	phosphorylation	up-regulates	0.307	The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency.	SIGNOR-22455
O15530	Q13464	0	phosphorylation	up-regulates activity	0.298	Additional phosphorylation of PDK1 by ROCK-I improves the stability of the ROCK-I and PDK1 complex.	SIGNOR-279758
P25098	P21462	1	phosphorylation	down-regulates activity	0.2	Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation.	SIGNOR-251452
P23458	P14784	2	phosphorylation	up-regulates activity	0.631	In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.	SIGNOR-251340
Q15796	Q4ZG55	2	binding	down-regulates activity	0.2	GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription	SIGNOR-265884
P46937	Q9NRM7	0	phosphorylation	down-regulates	0.821	Lats1/2 inhibit yap by direct phosphorylation at s127, which results in yap binding to 14-3-3 and cytoplasmic sequestration	SIGNOR-198514
P17252	P48048	1	phosphorylation	down-regulates activity	0.2	The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2).	SIGNOR-276389
Q13153	Q7Z628	1	phosphorylation	down-regulates activity	0.249	In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner.	SIGNOR-263018
Q9H1J7	Q9NPG1	2	binding	up-regulates	0.636	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141440
P08575	P68400	0	phosphorylation	up-regulates	0.442	Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein,	SIGNOR-65277
P31749	Q5S007	0	phosphorylation	up-regulates	0.379	Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling	SIGNOR-252598
Q9Y4K3	Q8N5C8	2	binding	up-regulates activity	0.714	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205461
P10275	P36952	1	transcriptional regulation	down-regulates quantity by repression	0.401	In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter	SIGNOR-253685
P84022	Q9Y5K5	0	deubiquitination	up-regulates activity	0.397	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases	SIGNOR-232101
Q92835	P32121	2	binding	up-regulates activity	0.2	We identified a new adaptor beta-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells.	SIGNOR-261428
Q15139	P48426	1	phosphorylation	down-regulates	0.2	We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases.	SIGNOR-145370
P00533	Q8NFJ5	1	phosphorylation	down-regulates activity	0.387	EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.\|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells.	SIGNOR-278336
Q15349	P28482	0	phosphorylation	up-regulates	0.717	Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-161515
O95786	Q13283	2	binding	down-regulates activity	0.338	G3BP1 binds RIG-I and that this interaction involves the C-terminal RGG domain of G3BP1, G3BP1 significantly enhances RIG-I-induced ifn-b mRNA synthesis.	SIGNOR-260980
P15923	Q02363	2	binding	down-regulates activity	0.585	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241140
P28482	Q8NHW3	1	phosphorylation	up-regulates activity	0.334	These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription.	SIGNOR-108564
P46821	P53355	2	binding	up-regulates	0.262	Dapk-1 interacts with the microtubule-associated protein map1b, in particular in conditions of amino-acid starvation.	SIGNOR-181305
O95886	Q9Y566	1	relocalization	up-regulates activity	0.8	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264592
Q16619	P42702	2	binding	up-regulates	0.731	We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1	SIGNOR-114758
Q9HCE7	O60716	1	monoubiquitination	down-regulates activity	0.2	Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.	SIGNOR-277507
P17612	Q7Z434	1	phosphorylation	down-regulates activity	0.283	Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).\|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G).	SIGNOR-279649
Q13239	P29317	2	binding	down-regulates quantity by destabilization	0.414	These data are consistent with a model where SLAP induces Ephrin-independent EPHA2 degradation. \| This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2.	SIGNOR-262964
Q9H4B4	Q99986	1	phosphorylation	up-regulates	0.474	Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process.	SIGNOR-182858
Q9UI33	P61328	2	binding	down-regulates activity	0.264	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-253436
Q5S007	O14966	1	phosphorylation	up-regulates activity	0.581	In an attempt to mimic phosphorylation of Rab29 by LRRK2, we mutated the phosphorylation sites to Glu and observed that the Rab29[T71E,S72E] mutant failed to activate LRRK2 (Fig\u00a0 xref B).\|To test whether phosphorylation of Rab29 at Thr71 and Ser72 by LRRK2 was required for activation of LRRK2, we mutated these sites both to Ala.	SIGNOR-279474
Q9UJV9	Q86WV6	2	binding	up-regulates activity	0.2	The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site.	SIGNOR-266403
P49840	P05412	1	phosphorylation	down-regulates	0.331	Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity.	SIGNOR-21780
Q96KS0	O43524	1	hydroxylation	down-regulates activity	0.287	Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.\|Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a.	SIGNOR-261998
P24666	Q05397	1	dephosphorylation	down-regulates activity	0.276	Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity. 4000254={CellProcess=4107155 CellType=10000184}}\|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways.	SIGNOR-277064
O75581	Q13467	2	binding	up-regulates activity	0.738	Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.	SIGNOR-258966
P53350	P51587	1	phosphorylation	down-regulates activity	0.539	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102486
P52306	P61586	2	binding	up-regulates	0.633	Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc	SIGNOR-171347
Q14451	Q06124	0	dephosphorylation	up-regulates activity	0.435	Dephosphorylation of Grb7 was blocked by the SHP inhibitor NSC-87877 (Zhan et al., 2009), supporting the specificity of SHP-2 in dephosphorylating Grb7.\|Nuclear SHP-2 mediates the formation of an EGF induced complex of Grb7, HuR, and CRM1.\|Using the \u03ba\u2013opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2\u2013containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus.	SIGNOR-277169
P12004	Q14527	0	ubiquitination	up-regulates activity	0.78	HLTF promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen (PCNA) that is required for maintaining genomic stability.	SIGNOR-278608
P67870	P18848	1	phosphorylation	down-regulates quantity by destabilization	0.2	By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.	SIGNOR-276424
Q9UI47	P35222	1	relocalization	up-regulates quantity	0.753	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265493
Q16584	Q13153	1	phosphorylation	up-regulates activity	0.304	Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3.\|MLK3 was able to directly phosphorylate PAK1 on two Serine residues of which Ser204 is critical for MLK3-induced PAK1 activation and downstream functions.	SIGNOR-279418
Q12967	Q92963	2	binding	up-regulates activity	0.534	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220859
Q5T7B8	P51955	0	phosphorylation	up-regulates activity	0.695	Nek2 binds and phosphorylates Kif24.\|We also provide evidence that Nek2 dependent phosphorylation induces a conformational change in Kif24 that promotes its activity.	SIGNOR-278413
O95622	P63096	2	binding	down-regulates activity	0.607	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278074
Q9Y297	P47736	1	ubiquitination	down-regulates	0.342	Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex.	SIGNOR-203548
P22455	Q8WU20	1	phosphorylation	up-regulates activity	0.685	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-242661
Q9UNE7	Q9NZQ7	1	destabilization	down-regulates quantity by destabilization	0.2	Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly	SIGNOR-274979
P67775	P84022	1	dephosphorylation	down-regulates	0.2	Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a.	SIGNOR-167480
O95996	P35222	1	relocalization	down-regulates quantity by destabilization	0.79	The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation.	SIGNOR-81545
P46020	P22694	0	phosphorylation	down-regulates activity	0.325	Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267413
Q02078	Q16539	0	phosphorylation	up-regulates activity	0.661	We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a	SIGNOR-62780
P16591	P16284	1	phosphorylation	up-regulates activity	0.322	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262866
P42345	P40763	1	phosphorylation	up-regulates	0.748	Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor	SIGNOR-146915
P04179	Q9NTG7	0	deacetylation	up-regulates activity	0.654	SOD2 is the key substrate of SIRT3 in mitochondria. The combination of SIRT3 and SOD2 leads to the deacetylation and activation of SOD2	SIGNOR-267646
Q06124	Q13480	1	dephosphorylation	down-regulates activity	0.952	These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.\|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.	SIGNOR-248674
P43116	P63092	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 ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256756
Q8TAK5	P51610	2	binding	down-regulates activity	0.2	The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1GABP interaction can inhibit GABP_dependent transcriptional activation	SIGNOR-221318
O15379	P24385	2	binding	up-regulates	0.412	Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function.	SIGNOR-134056
Q6UB99	P17677	1	transcriptional regulation	up-regulates quantity by expression	0.2	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.	SIGNOR-266736
P49675	P49715	0	transcriptional regulation	up-regulates quantity by expression	0.335	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254043
O95837	P11229	2	binding	up-regulates activity	0.402	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-257130
P35637	P57678	1	relocalization	up-regulates activity	0.2	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.\|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 \|Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262105
P63000	Q8IZD9	0	guanine nucleotide exchange factor	up-regulates activity	0.656	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260548
Q8TAD8	Q13485	2	binding	down-regulates	0.591	In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4	SIGNOR-78984
P30533	Q9NYY3	0	phosphorylation	up-regulates activity	0.3	Inhibition of Ras and activation of Rap by Plk2.\|Plk2 phosphorylation of Ras and Rap regulators controls surface AMPARs.	SIGNOR-279476
Q16820	P17252	0	phosphorylation	down-regulates quantity	0.2	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263172
P42574	P31749	1	cleavage	down-regulates activity	0.602	P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro	SIGNOR-252624
P28562	P45984	1	dephosphorylation	down-regulates	0.681	We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.	SIGNOR-40879
Q8WYL5	Q9BZL6	0	phosphorylation	down-regulates	0.291	Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.	SIGNOR-173441
Q16620	O43639	2	binding	up-regulates	0.335	We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction.	SIGNOR-89764
Q9H1K1	P42345	0	phosphorylation	up-regulates	0.2	Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein.	SIGNOR-201595
P63096	P30874	2	binding	up-regulates activity	0.582	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-256684
O14672	P35070	1	cleavage	up-regulates activity	0.372	Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin	SIGNOR-259839
P54274	Q9H2K2	0	ADP-ribosylation	down-regulates activity	0.549	Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres.	SIGNOR-263376
P30408	Q9H190	1	relocalization	up-regulates activity	0.402	TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2.	SIGNOR-272401
Q96P20	Q9HAT8	0	ubiquitination	up-regulates activity	0.2	Pellino2 promotes ubiquitination of NLRP3.\|We now demonstrate that Pellino2 can promote increased production of mature bioactive IL-1beta by facilitating activation of the NLRP3 inflammasome.	SIGNOR-278525
P12931	Q92558	1	phosphorylation	up-regulates	0.407	The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex	SIGNOR-142724
P46379	O43765	2	binding	up-regulates activity	0.467	USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.	SIGNOR-272859
P08151	P49757	2	binding	down-regulates	0.623	The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation.	SIGNOR-167841
P16885	P06241	0	phosphorylation	up-regulates activity	0.575	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249340
P42345	P00519	0	phosphorylation	down-regulates	0.453	Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k).	SIGNOR-76562
Q08050	P12931	0	phosphorylation	up-regulates activity	0.324	Hence, c-Src-dependent phosphorylation of MPP2 could be part of a negative feedback loop within the circuitry that modulates c-Src activity by MPP2.	SIGNOR-279117
P27361	Q13153	1	phosphorylation	down-regulates	0.337	Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.	SIGNOR-123074
Q9BXM7	P0CG48	1	phosphorylation	up-regulates activity	0.604	Ubiquitin is phosphorylated by PINK1 to activate parkin\|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells	SIGNOR-249691
Q96AQ6	Q14164	0	phosphorylation	down-regulates quantity by destabilization	0.2	Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.	SIGNOR-276618
Q16539	Q05923	0	dephosphorylation	down-regulates	0.623	We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively	SIGNOR-40918
O95140	P45984	0	phosphorylation	down-regulates	0.351	Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process	SIGNOR-198054
Q14242	P16581	2	binding	up-regulates	0.771	PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro.	SIGNOR-46330
Q04206	Q9Y6K9	0	phosphorylation	up-regulates activity	0.862	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129947
Q01484	O00555	2	binding	up-regulates quantity	0.263	Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo.	SIGNOR-266706
P40337	P12931	0	phosphorylation	down-regulates quantity by destabilization	0.29	We have found that elevated Src can trigger a drastic reduction in VHL stability even under normoxic conditions, through phosphorylation of VHL tyrosine residue 185, leading to ubiquitination and proteasome mediated degradation of VHL.	SIGNOR-279125
O75581	Q03431	2	binding	up-regulates	0.337	Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt.	SIGNOR-199533
Q13588	Q8WU20	2	binding	up-regulates	0.339	Complex formation between grb2 and frs2_ is mediated by y196, y306, y349, and y392 of frs2_ (designated direct grb2-binding sites;ref. 1). In addition, frs2_ recruits grb2 indirectly by means of the protein tyrosine phosphatase shp2 by way of residues y436 and y471 (designated shp2-binding sites;ref. 2).	SIGNOR-87169
Q99759	P45985	2	binding	up-regulates activity	0.604	These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3.	SIGNOR-48628
Q13393	P61586	2	binding	up-regulates	0.697	Our results demonstrate that direct stimulation of pld1 in vivo by rhoa	SIGNOR-84953
Q9P0L2	P27816	1	phosphorylation	down-regulates activity	0.437	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability.	SIGNOR-250171
Q9P104	P07949	2	binding	up-regulates	0.624	Dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase	SIGNOR-109516

P10747

P06239

0

phosphorylation

up-regulates

0.754

We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor

SIGNOR-45524

Q9Y5K5

Q15796

1

deubiquitination

up-regulates

0.378

Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases

SIGNOR-138876

P61925

P00533

0

phosphorylation

up-regulates

0.307

The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency.

SIGNOR-22455

O15530

Q13464

0

phosphorylation

up-regulates activity

0.298

Additional phosphorylation of PDK1 by ROCK-I improves the stability of the ROCK-I and PDK1 complex.

SIGNOR-279758

P25098

P21462

1

phosphorylation

down-regulates activity

0.2

Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation.

SIGNOR-251452

P23458

P14784

2

phosphorylation

up-regulates activity

0.631

In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.

SIGNOR-251340

Q15796

Q4ZG55

2

binding

down-regulates activity

0.2

GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription

SIGNOR-265884

P46937

Q9NRM7

0

phosphorylation

down-regulates

0.821

Lats1/2 inhibit yap by direct phosphorylation at s127, which results in yap binding to 14-3-3 and cytoplasmic sequestration

SIGNOR-198514

P17252

P48048

1

phosphorylation

down-regulates activity

0.2

The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2).

SIGNOR-276389

Q13153

Q7Z628

1

phosphorylation

down-regulates activity

0.249

In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner.

SIGNOR-263018

Q9H1J7

Q9NPG1

2

binding

up-regulates

0.636

Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.

SIGNOR-141440

P08575

P68400

0

phosphorylation

up-regulates

0.442

Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein,

SIGNOR-65277

P31749

Q5S007

0

phosphorylation

up-regulates

0.379

Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling

SIGNOR-252598

Q9Y4K3

Q8N5C8

2

binding

up-regulates activity

0.714

The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.

SIGNOR-205461

P10275

P36952

1

transcriptional regulation

down-regulates quantity by repression

0.401

In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter

SIGNOR-253685

P84022

Q9Y5K5

0

deubiquitination

up-regulates activity

0.397

Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases

SIGNOR-232101

Q92835

P32121

2

binding

up-regulates activity

0.2

We identified a new adaptor beta-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells.

SIGNOR-261428

Q15139

P48426

1

phosphorylation

down-regulates

0.2

We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases.

SIGNOR-145370

P00533

Q8NFJ5

1

phosphorylation

down-regulates activity

0.387

EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells.

SIGNOR-278336

Q15349

P28482

0

phosphorylation

up-regulates

0.717

Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.

SIGNOR-161515

O95786

Q13283

2

binding

down-regulates activity

0.338

G3BP1 binds RIG-I and that this interaction involves the C-terminal RGG domain of G3BP1, G3BP1 significantly enhances RIG-I-induced ifn-b mRNA synthesis.

SIGNOR-260980

P15923

Q02363

2

binding

down-regulates activity

0.585

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

SIGNOR-241140

P28482

Q8NHW3

1

phosphorylation

up-regulates activity

0.334

These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription.

SIGNOR-108564

P46821

P53355

2

binding

up-regulates

0.262

Dapk-1 interacts with the microtubule-associated protein map1b, in particular in conditions of amino-acid starvation.

SIGNOR-181305

O95886

Q9Y566

1

relocalization

up-regulates activity

0.8

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

SIGNOR-264592

Q16619

P42702

2

binding

up-regulates

0.731

We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1

SIGNOR-114758

Q9HCE7

O60716

1

monoubiquitination

down-regulates activity

0.2

Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.

SIGNOR-277507

P17612

Q7Z434

1

phosphorylation

down-regulates activity

0.283

Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G).

SIGNOR-279649

Q13239

P29317

2

binding

down-regulates quantity by destabilization

0.414

These data are consistent with a model where SLAP induces Ephrin-independent EPHA2 degradation. | This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2.

SIGNOR-262964

Q9H4B4

Q99986

1

phosphorylation

up-regulates

0.474

Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process.

SIGNOR-182858

Q9UI33

P61328

2

binding

down-regulates activity

0.264

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-253436

Q5S007

O14966

1

phosphorylation

up-regulates activity

0.581

In an attempt to mimic phosphorylation of Rab29 by LRRK2, we mutated the phosphorylation sites to Glu and observed that the Rab29[T71E,S72E] mutant failed to activate LRRK2 (Fig\u00a0 xref B).|To test whether phosphorylation of Rab29 at Thr71 and Ser72 by LRRK2 was required for activation of LRRK2, we mutated these sites both to Ala.

SIGNOR-279474

Q9UJV9

Q86WV6

2

binding

up-regulates activity

0.2

The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site.

SIGNOR-266403

P49840

P05412

1

phosphorylation

down-regulates

0.331

Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity.

SIGNOR-21780

Q96KS0

O43524

1

hydroxylation

down-regulates activity

0.287

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.|Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a.

SIGNOR-261998

P24666

Q05397

1

dephosphorylation

down-regulates activity

0.276

Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity. 4000254={CellProcess=4107155 CellType=10000184}}|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways.

SIGNOR-277064

O75581

Q13467

2

binding

up-regulates activity

0.738

Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.

SIGNOR-258966

P53350

P51587

1

phosphorylation

down-regulates activity

0.539

M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1

SIGNOR-102486

P52306

P61586

2

binding

up-regulates

0.633

Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc

SIGNOR-171347

Q14451

Q06124

0

dephosphorylation

up-regulates activity

0.435

Dephosphorylation of Grb7 was blocked by the SHP inhibitor NSC-87877 (Zhan et al., 2009), supporting the specificity of SHP-2 in dephosphorylating Grb7.|Nuclear SHP-2 mediates the formation of an EGF induced complex of Grb7, HuR, and CRM1.|Using the \u03ba\u2013opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2\u2013containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus.

SIGNOR-277169

P12004

Q14527

0

ubiquitination

up-regulates activity

0.78

HLTF promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen (PCNA) that is required for maintaining genomic stability.

SIGNOR-278608

P67870

P18848

1

phosphorylation

down-regulates quantity by destabilization

0.2

By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.

SIGNOR-276424

Q9UI47

P35222

1

relocalization

up-regulates quantity

0.753

Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14

SIGNOR-265493

Q16584

Q13153

1

phosphorylation

up-regulates activity

0.304

Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3.|MLK3 was able to directly phosphorylate PAK1 on two Serine residues of which Ser204 is critical for MLK3-induced PAK1 activation and downstream functions.

SIGNOR-279418

Q12967

Q92963

2

binding

up-regulates activity

0.534

Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.

SIGNOR-220859

Q5T7B8

P51955

0

phosphorylation

up-regulates activity

0.695

Nek2 binds and phosphorylates Kif24.|We also provide evidence that Nek2 dependent phosphorylation induces a conformational change in Kif24 that promotes its activity.

SIGNOR-278413

O95622

P63096

2

binding

down-regulates activity

0.607

Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3

SIGNOR-278074

Q9Y297

P47736

1

ubiquitination

down-regulates

0.342

Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex.

SIGNOR-203548

P22455

Q8WU20

1

phosphorylation

up-regulates activity

0.685

In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.

SIGNOR-242661

Q9UNE7

Q9NZQ7

1

destabilization

down-regulates quantity by destabilization

0.2

Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly

SIGNOR-274979

P67775

P84022

1

dephosphorylation

down-regulates

0.2

Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a.

SIGNOR-167480

O95996

P35222

1

relocalization

down-regulates quantity by destabilization

0.79

The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation.

SIGNOR-81545

P46020

P22694

0

phosphorylation

down-regulates activity

0.325

Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.

SIGNOR-267413

Q02078

Q16539

0

phosphorylation

up-regulates activity

0.661

We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a

SIGNOR-62780

P16591

P16284

1

phosphorylation

up-regulates activity

0.322

PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.

SIGNOR-262866

P42345

P40763

1

phosphorylation

up-regulates

0.748

Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor

SIGNOR-146915

P04179

Q9NTG7

0

deacetylation

up-regulates activity

0.654

SOD2 is the key substrate of SIRT3 in mitochondria. The combination of SIRT3 and SOD2 leads to the deacetylation and activation of SOD2

SIGNOR-267646

Q06124

Q13480

1

dephosphorylation

down-regulates activity

0.952

These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.

SIGNOR-248674

P43116

P63092

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 ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256756

Q8TAK5

P51610

2

binding

down-regulates activity

0.2

The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1GABP interaction can inhibit GABP_dependent transcriptional activation

SIGNOR-221318

O15379

P24385

2

binding

up-regulates

0.412

Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function.

SIGNOR-134056

Q6UB99

P17677

1

transcriptional regulation

up-regulates quantity by expression

0.2

Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.

SIGNOR-266736

P49675

P49715

0

transcriptional regulation

up-regulates quantity by expression

0.335

Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.

SIGNOR-254043

O95837

P11229

2

binding

up-regulates activity

0.402

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-257130

P35637

P57678

1

relocalization

up-regulates activity

0.2

Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells

SIGNOR-262105

P63000

Q8IZD9

0

guanine nucleotide exchange factor

up-regulates activity

0.656

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

SIGNOR-260548

Q8TAD8

Q13485

2

binding

down-regulates

0.591

In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4

SIGNOR-78984

P30533

Q9NYY3

0

phosphorylation

up-regulates activity

0.3

Inhibition of Ras and activation of Rap by Plk2.|Plk2 phosphorylation of Ras and Rap regulators controls surface AMPARs.

SIGNOR-279476

Q16820

P17252

0

phosphorylation

down-regulates quantity

0.2

These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.

SIGNOR-263172

P42574

P31749

1

cleavage

down-regulates activity

0.602

P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro

SIGNOR-252624

P28562

P45984

1

dephosphorylation

down-regulates

0.681

We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.

SIGNOR-40879

Q8WYL5

Q9BZL6

0

phosphorylation

down-regulates

0.291

Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.

SIGNOR-173441

Q16620

O43639

2

binding

up-regulates

0.335

We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction.

SIGNOR-89764

Q9H1K1

P42345

0

phosphorylation

up-regulates

0.2

Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein.

SIGNOR-201595

P63096

P30874

2

binding

up-regulates activity

0.582

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-256684

O14672

P35070

1

cleavage

up-regulates activity

0.372

Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin

SIGNOR-259839

P54274

Q9H2K2

0

ADP-ribosylation

down-regulates activity

0.549

Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres.

SIGNOR-263376

P30408

Q9H190

1

relocalization

up-regulates activity

0.402

TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2.

SIGNOR-272401

Q96P20

Q9HAT8

0

ubiquitination

up-regulates activity

0.2

Pellino2 promotes ubiquitination of NLRP3.|We now demonstrate that Pellino2 can promote increased production of mature bioactive IL-1beta by facilitating activation of the NLRP3 inflammasome.

SIGNOR-278525

P12931

Q92558

1

phosphorylation

up-regulates

0.407

The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex

SIGNOR-142724

P46379

O43765

2

binding

up-regulates activity

0.467

USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.

SIGNOR-272859

P08151

P49757

2

binding

down-regulates

0.623

The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation.

SIGNOR-167841

P16885

P06241

0

phosphorylation

up-regulates activity

0.575

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-249340

P42345

P00519

0

phosphorylation

down-regulates

0.453

Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k).

SIGNOR-76562

Q08050

P12931

0

phosphorylation

up-regulates activity

0.324

Hence, c-Src-dependent phosphorylation of MPP2 could be part of a negative feedback loop within the circuitry that modulates c-Src activity by MPP2.

SIGNOR-279117

P27361

Q13153

1

phosphorylation

down-regulates

0.337

Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.

SIGNOR-123074

Q9BXM7

P0CG48

1

phosphorylation

up-regulates activity

0.604

Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells

SIGNOR-249691

Q96AQ6

Q14164

0

phosphorylation

down-regulates quantity by destabilization

0.2

Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.

SIGNOR-276618

Q16539

Q05923

0

dephosphorylation

down-regulates

0.623

We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively

SIGNOR-40918

O95140

P45984

0

phosphorylation

down-regulates

0.351

Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process

SIGNOR-198054

Q14242

P16581

2

binding

up-regulates

0.771

PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro.

SIGNOR-46330

Q04206

Q9Y6K9

0

phosphorylation

up-regulates activity

0.862

Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.

SIGNOR-129947

Q01484

O00555

2

binding

up-regulates quantity

0.263

Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo.

SIGNOR-266706

P40337

P12931

0

phosphorylation

down-regulates quantity by destabilization

0.29

We have found that elevated Src can trigger a drastic reduction in VHL stability even under normoxic conditions, through phosphorylation of VHL tyrosine residue 185, leading to ubiquitination and proteasome mediated degradation of VHL.

SIGNOR-279125

O75581

Q03431

2

binding

up-regulates

0.337

Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt.

SIGNOR-199533

Q13588

Q8WU20

2

binding

up-regulates

0.339

Complex formation between grb2 and frs2_ is mediated by y196, y306, y349, and y392 of frs2_ (designated direct grb2-binding sites;ref. 1). In addition, frs2_ recruits grb2 indirectly by means of the protein tyrosine phosphatase shp2 by way of residues y436 and y471 (designated shp2-binding sites;ref. 2).

SIGNOR-87169

Q99759

P45985

2

binding

up-regulates activity

0.604

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

SIGNOR-48628

Q13393

P61586

2

binding

up-regulates

0.697

Our results demonstrate that direct stimulation of pld1 in vivo by rhoa

SIGNOR-84953

Q9P0L2

P27816

1

phosphorylation

down-regulates activity

0.437

Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability.

SIGNOR-250171

Q9P104

P07949

2

binding

up-regulates

0.624

Dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase

SIGNOR-109516