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
P23025	Q13535	0	phosphorylation	up-regulates activity	0.492	ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215.	SIGNOR-258985
P31749	Q00613	1	phosphorylation	up-regulates activity	0.405	Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.	SIGNOR-277579
P49840	P20749	1	phosphorylation	down-regulates quantity by destabilization	0.392	In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway.	SIGNOR-276011
Q9GZQ4	P63096	2	binding	up-regulates activity	0.435	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256731
P06241	Q99835	0	phosphorylation	up-regulates	0.425	Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion.	SIGNOR-199156
P27361	P01106	1	phosphorylation	up-regulates activity	0.707	ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation	SIGNOR-236250
O95140	Q7Z6Z7	0	ubiquitination	down-regulates quantity by destabilization	0.42	AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome	SIGNOR-272978
O60331	Q00535	0	phosphorylation	down-regulates	0.364	The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type i gamma (pipki gamma) regulates pi(4,5)p2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (s650) within the talin-binding sequence of human pipki gamma blocks this interaction. At synapses, s650 is phosphorylated by p35/cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation.	SIGNOR-134455
P06493	Q16665	1	phosphorylation	up-regulates activity	0.274	In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1\u03b1 at a previously unidentified regulatory site, Ser668.\|Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1alpha under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1alpha, reducing its half-life and steady-state levels.	SIGNOR-279599
P53779	P63104	1	phosphorylation	down-regulates	0.2	Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190	SIGNOR-124009
P45983	P45985	0	phosphorylation	up-regulates activity	0.752	Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1).	SIGNOR-251419
P53992	Q9NR31	2	binding	up-regulates quantity	0.709	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.	SIGNOR-265302
Q13501	P50542	2	binding	up-regulates activity	0.372	Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.	SIGNOR-262793
P06241	P56945	1	phosphorylation	up-regulates activity	0.766	Taken together, these results suggest that p130Cas is directly phosphorylated by Fyn kinase in the cytoplasm of oligodendrocytes.	SIGNOR-279372
Q92630	Q00613	1	phosphorylation	up-regulates activity	0.318	To test whether in a similar way DYRK2 phosphorylates and activates HSF1 in human cancer cells, we overexpressed DYRK2 and, by use of phosphospecific antibodies, we observed that the levels of endogenous HSF1 phosphorylated at S326 and S320 (two main phosphorylation events linked to HSF1 activation) were increased (Fig.\u00a0 xref ).\|Together, these results show that DYRK2 phosphorylates HSF1 in cells and in vitro at S320 and also at S326, which is critical for HSF1 activation.Next, to test whether endogenous DYRK2 plays a role in HSF1 activation by proteotoxic stress, we used the prototypical HSF1 inducer heat shock (HS), in the absence or in the presence of harmine, observing that the inhibitor clearly impaired the phosphorylation of HSF1 upon HS (Fig S1F).	SIGNOR-278355
Q7L7X3	P46734	1	phosphorylation	up-regulates activity	0.578	The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway	SIGNOR-60818
P68400	P08238	1	phosphorylation	down-regulates	0.333	Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation.	SIGNOR-179264
Q00987	Q9Y294	1	ubiquitination	down-regulates quantity by destabilization	0.267	We found that MDM2 overexpression also decreased the ASF1A half-life time, indicating an accelerated ASF1A degradation.\|We next examined whether the presence of RAD6 is essential for MDM2-induced ASF1A ubiquitination.	SIGNOR-278822
P42574	O15392	2	binding	down-regulates	0.489	Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21.	SIGNOR-72882
Q13485	Q8TAD8	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
P48736	P29376	2	binding	up-regulates	0.254	Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85	SIGNOR-49622
P03372	P06401	2	binding	up-regulates	0.624	Here we identify two domains of prb, erid-i and -ii, mediating a direct interaction with the ligand-binding domain of eralpha.	SIGNOR-98807
Q9Y6H6	Q05655	0	phosphorylation	up-regulates activity	0.2	Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit (mutation of the site for PKCdelta-promoted phosphorylation and modulation of the activity of KCNE3) showed rapid run-down and insensitivity to E2.	SIGNOR-275964
Q5FBB7	P51955	0	phosphorylation	up-regulates	0.2	Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)	SIGNOR-156882
P35232	P10721	0	phosphorylation	up-regulates activity	0.2	In this study, we showed that c-Kit associates with PHB to upregulate phospho-PHB in the lipid raft of the plasma membrane.\|c-Kit phosphorylates PHB at the Tyr259 residue.	SIGNOR-278362
O75582	P54253	1	phosphorylation	up-regulates quantity by stabilization	0.26	In summary, the data from the cell based screen, biochemical studies and genetic interactions strongly suggest that MSK1 phosphorylates ATXN1 and regulates its stability.	SIGNOR-279109
P32245	P19086	2	binding	up-regulates activity	0.252	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-257270
P53350	P49137	0	phosphorylation	up-regulates	0.349	Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase.	SIGNOR-179968
Q8IXJ9	P10276	2	binding	up-regulates activity	0.444	Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.	SIGNOR-255910
Q00613	Q04759	0	phosphorylation	up-regulates	0.349	At the same time, ea causes pkc?-Mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence.	SIGNOR-200576
P04150	O15534	1	transcriptional regulation	up-regulates quantity by expression	0.268	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268050
O95644	P45983	0	phosphorylation	down-regulates activity	0.621	It has been previously shown that NF-ATc1 accumulates in the nucleus of activated CD4 + T cells from Jnk1 \n \u2212/\u2212 mice 35\u2022 and that JNK1 phosphorylates and inactivates NFATc1 in Jurkat T cells 47 , indicating that JNK1 is an inhibitor of NFAT.	SIGNOR-280031
P49418	P27361	0	phosphorylation	down-regulates activity	0.274	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-126867
P21860	P42336	2	binding	up-regulates	0.708	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146861
P23458	P29350	0	dephosphorylation	down-regulates	0.646	We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation.	SIGNOR-119197
Q16659	Q16659	2	phosphorylation	up-regulates	0.2	Ser189 of erk3, which corresponds to thr183, one of the activating phosphorylation sites of erk2, is autophosphorylated in vitro and phosphorylated in vivo.	SIGNOR-40097
P40424	P15172	2	binding	up-regulates activity	0.41	These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site	SIGNOR-124834
Q02078	Q9UKX2	1	transcriptional regulation	up-regulates quantity by expression	0.325	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238703
Q13972	P12931	0	phosphorylation	down-regulates activity	0.47	These proximal Src kinases could potentially directly or indirectly phosphorylate Rasgrf-1 upon BCR activation and thereby further increase its GEF activity.	SIGNOR-280133
Q8NB16	Q06418	0	phosphorylation	up-regulates quantity by stabilization	0.2	TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6).	SIGNOR-274120
Q92911	P27695	0	transcriptional regulation	up-regulates quantity by expression	0.2	These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8.	SIGNOR-261564
P26358	P06493	0	phosphorylation	up-regulates	0.3	We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5	SIGNOR-173677
Q9ULV8	O15197	2	binding	up-regulates activity	0.274	We suggest that although mammalian EphB6 is kinase-negative, it has retained the allosteric regulatory mechanisms involving the juxtamembrane and the SAM domain linker that are used to regulate the kinase activity of kinase-active Eph receptors. he inability to recruit c-Cbl by EphB6 meant that heightened levels of EphA2 remained active in the cell because they had evaded c-Cbl-mediated degradation. The authors suggest that mutation of residues 901–926 within EphB6 reduces the flexibility of the SAM domain such that c-Cbl cannot be recruited.	SIGNOR-273852
P04150	P19838	1	transcriptional regulation	down-regulates quantity by repression	0.6	We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins	SIGNOR-251680
Q92843	O43521	2	binding	down-regulates	0.783	Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133832
P68400	Q16543	1	phosphorylation	up-regulates activity	0.397	Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. \| In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site.	SIGNOR-250838
O60716	P07333	0	phosphorylation	up-regulates quantity by stabilization	0.27	In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref ).	SIGNOR-278929
Q03468	Q96FI4	2	binding	up-regulates activity	0.344	CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells.	SIGNOR-251931
P30411	P01042	2	binding	up-regulates activity	0.857	BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis.	SIGNOR-263554
P49023	Q13418	2	binding	up-regulates	0.799	Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events.	SIGNOR-106824
P28482	Q9Y463	1	phosphorylation	up-regulates activity	0.369	S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro.	SIGNOR-276937
Q15139	P29475	1	phosphorylation	up-regulates activity	0.385	In addition, we demonstrate that protein kinase D1 activates nNOS by phosphorylating the activatory residue Ser1412, leading to increased \u00b7NO production, hence establishing a novel role of PKD in the regulation of \u00b7NO synthesis.\|PKD1 phosphorylates nNOS at activatory Ser 1412 in vitro and in live cells.	SIGNOR-278426
P05787	Q15759	0	phosphorylation	up-regulates	0.427	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114063
Q06413	Q92831	2	binding	up-regulates	0.573	The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.	SIGNOR-84032
O15111	P31751	0	phosphorylation	up-regulates	0.529	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187010
P53041	Q03113	2	binding	up-regulates activity	0.326	In this study, we show that active forms of Gna12 and Gna13 specifically interact with PP5 through its TPR domain and activate its phosphatase activity about 2.5-fold.	SIGNOR-278080
O00221	P19838	2	binding	down-regulates	0.541	Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe	SIGNOR-102774
P84022	P36897	0	phosphorylation	up-regulates activity	0.812	A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus	SIGNOR-235380
P42768	P68400	0	phosphorylation	up-regulates	0.354	Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule.	SIGNOR-101268
Q15848	Q8NBJ5	0	palmitoylation	up-regulates activity	0.2	We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity.	SIGNOR-261149
P12830	O75581	2	binding	up-regulates	0.363	P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin.	SIGNOR-168464
P35680	P16220	2	binding	up-regulates activity	0.373	The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays.	SIGNOR-241323
Q13873	O00238	2	binding	up-regulates	0.625	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii).	SIGNOR-75655
P60852	Q5JUK2	0	transcriptional regulation	up-regulates quantity by expression	0.2	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266077
Q16555	Q00535	0	phosphorylation	down-regulates activity	0.655	Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518\|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition	SIGNOR-264838
P32245	Q5JWF2	1	null	up-regulates activity	0.521	We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.	SIGNOR-253067
Q13257	P51955	0	phosphorylation	down-regulates activity	0.845	We demonstrated that overexpression of Nek2 can enhance the ability of Mad2 to cause delays in cell division.\|We have demonstrated that Nek2 can bind and phosphorylate Mad2 and Cdc20.	SIGNOR-278446
Q13163	Q99759	0	phosphorylation	up-regulates	0.72	Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.	SIGNOR-104637
O43283	O14733	1	phosphorylation	up-regulates	0.584	Lzk directly phosphorylated and activated mkk7.	SIGNOR-112349
P38405	P25021	2	binding	up-regulates activity	0.375	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-256920
P28482	Q92974	1	phosphorylation	up-regulates	0.358	Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation.	SIGNOR-184469
Q9UPC5	P08754	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256831
O95747	Q13621	1	phosphorylation	up-regulates activity	0.502	We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276309
Q9NRA0	P28482	0	phosphorylation	up-regulates	0.451	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-153383
O95837	P25103	2	binding	up-regulates activity	0.433	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-257423
Q9UIC8	P67775	1	methylation	up-regulates activity	0.908	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits \|The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)	SIGNOR-265749
P63215	P19174	2	binding	up-regulates	0.2	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199141
P34130	P04629	2	binding	up-regulates	0.693	Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.	SIGNOR-85117
P10636	P02649	2	binding	up-regulates activity	0.567	Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.\|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3.	SIGNOR-262588
P15056	Q92963	2	binding	up-regulates activity	0.55	It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development.	SIGNOR-251650
P52799	P54753	2	binding	up-regulates	0.883	Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation	SIGNOR-52583
P61978	P53779	0	phosphorylation	up-regulates activity	0.339	JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein.	SIGNOR-250083
P51610	Q13105	2	binding	down-regulates activity	0.344	We show here that HCF-1 directly binds to the Myc-interacting protein Miz-1. HCF-1 Represses Gal4-Miz-1-mediated Transcriptional Activation	SIGNOR-223590
P43320	P53674	2	binding	up-regulates activity	0.2	At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.	SIGNOR-252153
O15143	O14965	0	phosphorylation	up-regulates activity	0.46	Aurora A phosphorylates Arpc1b on threonine 21, and expression of Arpc1b but not a nonphosphorylatable Arpc1b mutant in mammalian cells leads to Aurora A kinase activation and abnormal centrosome amplification in a Pak1-independent manner.	SIGNOR-279438
O60602	Q15139	0	phosphorylation	up-regulates	0.353	Pkd phosphorylated the tlr5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in hek 293t cell-derived tlr5 was identified by mass spectrometry. These results demonstrate that both pkd1 and pkd2 are required for inflammatory responses following tlr2, tlr4, or tlr5 activation, although pkd1 is more strongly involved	SIGNOR-154473
Q13177	P49593	0	dephosphorylation	down-regulates	0.261	Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity.	SIGNOR-162149
Q8IX90	P06493	0	phosphorylation	up-regulates activity	0.394	Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].\|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization.	SIGNOR-278376
P45985	Q12852	0	phosphorylation	up-regulates activity	0.572	As expected, DLK significantly increased MKK4 phosphorylation on Ser257 / Thr261, and myrAKT1 enhanced MKK4 phosphorylation on Ser78 (XREF_FIG).\|While MKK4 activated by DLK had strong activity in phosphorylating JNK3, MKK4 expressed with DLK and AKT1 together exhibited little activity, even though the two samples had similar levels of Ser257 / Thr261 phosphorylation (XREF_FIG).	SIGNOR-279629
P78352	Q06787	0	post transcriptional regulation	up-regulates quantity	0.473	These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.	SIGNOR-262108
P18848	P67870	0	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
O14965	Q9NQS7	2	phosphorylation	up-regulates activity	0.693	INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop	SIGNOR-252047
P15509	P04141	2	binding	up-regulates	0.857	We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence.	SIGNOR-72458
P99999	Q16611	0	relocalization	up-regulates	0.566	Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux	SIGNOR-105206
O60331	P23443	0	phosphorylation	down-regulates quantity by destabilization	0.2	Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation.	SIGNOR-277283
O95835	P60891	1	phosphorylation	down-regulates quantity by destabilization	0.2	Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.	SIGNOR-276505
P78352	Q9C0D5	2	binding	up-regulates activity	0.596	In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.	SIGNOR-266894
O75581	P98082	2	binding	down-regulates	0.495	Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin.	SIGNOR-196925
O95837	Q9UBY5	2	binding	up-regulates activity	0.5	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-257357
P32121	P08588	2	binding	down-regulates activity	0.469	The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors	SIGNOR-256502

P23025

Q13535

0

phosphorylation

up-regulates activity

0.492

ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215.

SIGNOR-258985

P31749

Q00613

1

phosphorylation

up-regulates activity

0.405

Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.

SIGNOR-277579

P49840

P20749

1

phosphorylation

down-regulates quantity by destabilization

0.392

In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway.

SIGNOR-276011

Q9GZQ4

P63096

2

binding

up-regulates activity

0.435

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

SIGNOR-256731

P06241

Q99835

0

phosphorylation

up-regulates

0.425

Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion.

SIGNOR-199156

P27361

P01106

1

phosphorylation

up-regulates activity

0.707

ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation

SIGNOR-236250

O95140

Q7Z6Z7

0

ubiquitination

down-regulates quantity by destabilization

0.42

AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome

SIGNOR-272978

O60331

Q00535

0

phosphorylation

down-regulates

0.364

The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type i gamma (pipki gamma) regulates pi(4,5)p2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (s650) within the talin-binding sequence of human pipki gamma blocks this interaction. At synapses, s650 is phosphorylated by p35/cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation.

SIGNOR-134455

P06493

Q16665

1

phosphorylation

up-regulates activity

0.274

In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1\u03b1 at a previously unidentified regulatory site, Ser668.|Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1alpha under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1alpha, reducing its half-life and steady-state levels.

SIGNOR-279599

P53779

P63104

1

phosphorylation

down-regulates

0.2

Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190

SIGNOR-124009

P45983

P45985

0

phosphorylation

up-regulates activity

0.752

Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1).

SIGNOR-251419

P53992

Q9NR31

2

binding

up-regulates quantity

0.709

Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.

SIGNOR-265302

Q13501

P50542

2

binding

up-regulates activity

0.372

Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.

SIGNOR-262793

P06241

P56945

1

phosphorylation

up-regulates activity

0.766

Taken together, these results suggest that p130Cas is directly phosphorylated by Fyn kinase in the cytoplasm of oligodendrocytes.

SIGNOR-279372

Q92630

Q00613

1

phosphorylation

up-regulates activity

0.318

To test whether in a similar way DYRK2 phosphorylates and activates HSF1 in human cancer cells, we overexpressed DYRK2 and, by use of phosphospecific antibodies, we observed that the levels of endogenous HSF1 phosphorylated at S326 and S320 (two main phosphorylation events linked to HSF1 activation) were increased (Fig.\u00a0 xref ).|Together, these results show that DYRK2 phosphorylates HSF1 in cells and in vitro at S320 and also at S326, which is critical for HSF1 activation.Next, to test whether endogenous DYRK2 plays a role in HSF1 activation by proteotoxic stress, we used the prototypical HSF1 inducer heat shock (HS), in the absence or in the presence of harmine, observing that the inhibitor clearly impaired the phosphorylation of HSF1 upon HS (Fig S1F).

SIGNOR-278355

Q7L7X3

P46734

1

phosphorylation

up-regulates activity

0.578

The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway

SIGNOR-60818

P68400

P08238

1

phosphorylation

down-regulates

0.333

Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation.

SIGNOR-179264

Q00987

Q9Y294

1

ubiquitination

down-regulates quantity by destabilization

0.267

We found that MDM2 overexpression also decreased the ASF1A half-life time, indicating an accelerated ASF1A degradation.|We next examined whether the presence of RAD6 is essential for MDM2-induced ASF1A ubiquitination.

SIGNOR-278822

P42574

O15392

2

binding

down-regulates

0.489

Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21.

SIGNOR-72882

Q13485

Q8TAD8

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

P48736

P29376

2

binding

up-regulates

0.254

Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85

SIGNOR-49622

P03372

P06401

2

binding

up-regulates

0.624

Here we identify two domains of prb, erid-i and -ii, mediating a direct interaction with the ligand-binding domain of eralpha.

SIGNOR-98807

Q9Y6H6

Q05655

0

phosphorylation

up-regulates activity

0.2

Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit (mutation of the site for PKCdelta-promoted phosphorylation and modulation of the activity of KCNE3) showed rapid run-down and insensitivity to E2.

SIGNOR-275964

Q5FBB7

P51955

0

phosphorylation

up-regulates

0.2

Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)

SIGNOR-156882

P35232

P10721

0

phosphorylation

up-regulates activity

0.2

In this study, we showed that c-Kit associates with PHB to upregulate phospho-PHB in the lipid raft of the plasma membrane.|c-Kit phosphorylates PHB at the Tyr259 residue.

SIGNOR-278362

O75582

P54253

1

phosphorylation

up-regulates quantity by stabilization

0.26

In summary, the data from the cell based screen, biochemical studies and genetic interactions strongly suggest that MSK1 phosphorylates ATXN1 and regulates its stability.

SIGNOR-279109

P32245

P19086

2

binding

up-regulates activity

0.252

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-257270

P53350

P49137

0

phosphorylation

up-regulates

0.349

Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase.

SIGNOR-179968

Q8IXJ9

P10276

2

binding

up-regulates activity

0.444

Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.

SIGNOR-255910

Q00613

Q04759

0

phosphorylation

up-regulates

0.349

At the same time, ea causes pkc?-Mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence.

SIGNOR-200576

P04150

O15534

1

transcriptional regulation

up-regulates quantity by expression

0.268

GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription

SIGNOR-268050

O95644

P45983

0

phosphorylation

down-regulates activity

0.621

It has been previously shown that NF-ATc1 accumulates in the nucleus of activated CD4 + T cells from Jnk1 \n \u2212/\u2212 mice 35\u2022 and that JNK1 phosphorylates and inactivates NFATc1 in Jurkat T cells 47 , indicating that JNK1 is an inhibitor of NFAT.

SIGNOR-280031

P49418

P27361

0

phosphorylation

down-regulates activity

0.274

Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.

SIGNOR-126867

P21860

P42336

2

binding

up-regulates

0.708

Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.

SIGNOR-146861

P23458

P29350

0

dephosphorylation

down-regulates

0.646

We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation.

SIGNOR-119197

Q16659

2

phosphorylation

up-regulates

0.2

Ser189 of erk3, which corresponds to thr183, one of the activating phosphorylation sites of erk2, is autophosphorylated in vitro and phosphorylated in vivo.

SIGNOR-40097

P40424

P15172

2

binding

up-regulates activity

0.41

These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site

SIGNOR-124834

Q02078

Q9UKX2

1

transcriptional regulation

up-regulates quantity by expression

0.325

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238703

Q13972

P12931

0

phosphorylation

down-regulates activity

0.47

These proximal Src kinases could potentially directly or indirectly phosphorylate Rasgrf-1 upon BCR activation and thereby further increase its GEF activity.

SIGNOR-280133

Q8NB16

Q06418

0

phosphorylation

up-regulates quantity by stabilization

0.2

TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6).

SIGNOR-274120

Q92911

P27695

0

transcriptional regulation

up-regulates quantity by expression

0.2

These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8.

SIGNOR-261564

P26358

P06493

0

phosphorylation

up-regulates

0.3

We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5

SIGNOR-173677

Q9ULV8

O15197

2

binding

up-regulates activity

0.274

We suggest that although mammalian EphB6 is kinase-negative, it has retained the allosteric regulatory mechanisms involving the juxtamembrane and the SAM domain linker that are used to regulate the kinase activity of kinase-active Eph receptors. he inability to recruit c-Cbl by EphB6 meant that heightened levels of EphA2 remained active in the cell because they had evaded c-Cbl-mediated degradation. The authors suggest that mutation of residues 901–926 within EphB6 reduces the flexibility of the SAM domain such that c-Cbl cannot be recruited.

SIGNOR-273852

P04150

P19838

1

transcriptional regulation

down-regulates quantity by repression

0.6

We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins

SIGNOR-251680

Q92843

O43521

2

binding

down-regulates

0.783

Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.

SIGNOR-133832

P68400

Q16543

1

phosphorylation

up-regulates activity

0.397

Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site.

SIGNOR-250838

O60716

P07333

0

phosphorylation

up-regulates quantity by stabilization

0.27

In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref ).

SIGNOR-278929

Q03468

Q96FI4

2

binding

up-regulates activity

0.344

CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells.

SIGNOR-251931

P30411

P01042

2

binding

up-regulates activity

0.857

BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis.

SIGNOR-263554

P49023

Q13418

2

binding

up-regulates

0.799

Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events.

SIGNOR-106824

P28482

Q9Y463

1

phosphorylation

up-regulates activity

0.369

S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro.

SIGNOR-276937

Q15139

P29475

1

phosphorylation

up-regulates activity

0.385

In addition, we demonstrate that protein kinase D1 activates nNOS by phosphorylating the activatory residue Ser1412, leading to increased \u00b7NO production, hence establishing a novel role of PKD in the regulation of \u00b7NO synthesis.|PKD1 phosphorylates nNOS at activatory Ser 1412 in vitro and in live cells.

SIGNOR-278426

P05787

Q15759

0

phosphorylation

up-regulates

0.427

Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.

SIGNOR-114063

Q06413

Q92831

2

binding

up-regulates

0.573

The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.

SIGNOR-84032

O15111

P31751

0

phosphorylation

up-regulates

0.529

Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta

SIGNOR-187010

P53041

Q03113

2

binding

up-regulates activity

0.326

In this study, we show that active forms of Gna12 and Gna13 specifically interact with PP5 through its TPR domain and activate its phosphatase activity about 2.5-fold.

SIGNOR-278080

O00221

P19838

2

binding

down-regulates

0.541

Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe

SIGNOR-102774

P84022

P36897

0

phosphorylation

up-regulates activity

0.812

A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus

SIGNOR-235380

P42768

P68400

0

phosphorylation

up-regulates

0.354

Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule.

SIGNOR-101268

Q15848

Q8NBJ5

0

palmitoylation

up-regulates activity

0.2

We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity.

SIGNOR-261149

P12830

O75581

2

binding

up-regulates

0.363

P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin.

SIGNOR-168464

P35680

P16220

2

binding

up-regulates activity

0.373

The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays.

SIGNOR-241323

Q13873

O00238

2

binding

up-regulates

0.625

Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii).

SIGNOR-75655

P60852

Q5JUK2

0

transcriptional regulation

up-regulates quantity by expression

0.2

Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.

SIGNOR-266077

Q16555

Q00535

0

phosphorylation

down-regulates activity

0.655

Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition

SIGNOR-264838

P32245

Q5JWF2

1

null

up-regulates activity

0.521

We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.

SIGNOR-253067

Q13257

P51955

0

phosphorylation

down-regulates activity

0.845

We demonstrated that overexpression of Nek2 can enhance the ability of Mad2 to cause delays in cell division.|We have demonstrated that Nek2 can bind and phosphorylate Mad2 and Cdc20.

SIGNOR-278446

Q13163

Q99759

0

phosphorylation

up-regulates

0.72

Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.

SIGNOR-104637

O43283

O14733

1

phosphorylation

up-regulates

0.584

Lzk directly phosphorylated and activated mkk7.

SIGNOR-112349

P38405

P25021

2

binding

up-regulates activity

0.375

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-256920

P28482

Q92974

1

phosphorylation

up-regulates

0.358

Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation.

SIGNOR-184469

Q9UPC5

P08754

2

binding

up-regulates activity

0.2

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

SIGNOR-256831

O95747

Q13621

1

phosphorylation

up-regulates activity

0.502

We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).

SIGNOR-276309

Q9NRA0

P28482

0

phosphorylation

up-regulates

0.451

Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1

SIGNOR-153383

O95837

P25103

2

binding

up-regulates activity

0.433

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-257423

Q9UIC8

P67775

1

methylation

up-regulates activity

0.908

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)

SIGNOR-265749

P63215

P19174

2

binding

up-regulates

0.2

Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.

SIGNOR-199141

P34130

P04629

2

binding

up-regulates

0.693

Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.

SIGNOR-85117

P10636

P02649

2

binding

up-regulates activity

0.567

Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3.

SIGNOR-262588

P15056

Q92963

2

binding

up-regulates activity

0.55

It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development.

SIGNOR-251650

P52799

P54753

2

binding

up-regulates

0.883

Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation

SIGNOR-52583

P61978

P53779

0

phosphorylation

up-regulates activity

0.339

JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein.

SIGNOR-250083

P51610

Q13105

2

binding

down-regulates activity

0.344

We show here that HCF-1 directly binds to the Myc-interacting protein Miz-1. HCF-1 Represses Gal4-Miz-1-mediated Transcriptional Activation

SIGNOR-223590

P43320

P53674

2

binding

up-regulates activity

0.2

At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.

SIGNOR-252153

O15143

O14965

0

phosphorylation

up-regulates activity

0.46

Aurora A phosphorylates Arpc1b on threonine 21, and expression of Arpc1b but not a nonphosphorylatable Arpc1b mutant in mammalian cells leads to Aurora A kinase activation and abnormal centrosome amplification in a Pak1-independent manner.

SIGNOR-279438

O60602

Q15139

0

phosphorylation

up-regulates

0.353

Pkd phosphorylated the tlr5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in hek 293t cell-derived tlr5 was identified by mass spectrometry. These results demonstrate that both pkd1 and pkd2 are required for inflammatory responses following tlr2, tlr4, or tlr5 activation, although pkd1 is more strongly involved

SIGNOR-154473

Q13177

P49593

0

dephosphorylation

down-regulates

0.261

Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity.

SIGNOR-162149

Q8IX90

P06493

0

phosphorylation

up-regulates activity

0.394

Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization.

SIGNOR-278376

P45985

Q12852

0

phosphorylation

up-regulates activity

0.572

As expected, DLK significantly increased MKK4 phosphorylation on Ser257 / Thr261, and myrAKT1 enhanced MKK4 phosphorylation on Ser78 (XREF_FIG).|While MKK4 activated by DLK had strong activity in phosphorylating JNK3, MKK4 expressed with DLK and AKT1 together exhibited little activity, even though the two samples had similar levels of Ser257 / Thr261 phosphorylation (XREF_FIG).

SIGNOR-279629

P78352

Q06787

0

post transcriptional regulation

up-regulates quantity

0.473

These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.

SIGNOR-262108

P18848

P67870

0

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

O14965

Q9NQS7

2

phosphorylation

up-regulates activity

0.693

INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop

SIGNOR-252047

P15509

P04141

2

binding

up-regulates

0.857

We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence.

SIGNOR-72458

P99999

Q16611

0

relocalization

up-regulates

0.566

Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux

SIGNOR-105206

O60331

P23443

0

phosphorylation

down-regulates quantity by destabilization

0.2

Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation.

SIGNOR-277283

O95835

P60891

1

phosphorylation

down-regulates quantity by destabilization

0.2

Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.

SIGNOR-276505

P78352

Q9C0D5

2

binding

up-regulates activity

0.596

In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.

SIGNOR-266894

O75581

P98082

2

binding

down-regulates

0.495

Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin.

SIGNOR-196925

O95837

Q9UBY5

2

binding

up-regulates activity

0.5

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-257357

P32121

P08588

2

binding

down-regulates activity

0.469

The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors

SIGNOR-256502