GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q96PY6	Q9UKI8	phosphorylation	up-regulates activity	0.29	TLK1 phosphorylated NEK1 at T141, which lies in the kinase domain, and caused an increase in its activity.	SIGNOR-275840
P05204	P51812	phosphorylation	down-regulates activity	0.29	We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.	SIGNOR-249102
Q9Y2J4	Q9H0M0	ubiquitination	up-regulates activity	0.29	AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation\|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408.	SIGNOR-271873
P46527	P36888	phosphorylation	down-regulates activity	0.29	FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia\|P27Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88.	SIGNOR-269208
Q5JVS0	P05771	phosphorylation	down-regulates activity	0.29	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249247
P05204	P17252	phosphorylation	down-regulates	0.29	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76320
Q96P20	P07948	phosphorylation	down-regulates	0.29	Lyn phosphorylates NLRP3 at Tyr 918 and controls NLRP3 ubiquitination.\|Therefore, our data collectively indicate that Lyn inhibits the NLRP3 inflammasome in vivo.	SIGNOR-278485
Q92974	P27361	phosphorylation	up-regulates	0.29	Activates rhoa and as a result regulates actin assembly.	SIGNOR-160420
P13611	P04637	transcriptional regulation	up-regulates quantity by expression	0.29	By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53.	SIGNOR-255441
P40337	P12931	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
P46531	P51608	transcriptional regulation	down-regulates quantity by repression	0.29	As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1	SIGNOR-264675
Q8TD08	P67775	dephosphorylation	down-regulates	0.289	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%	SIGNOR-142977
P46527	P49336	phosphorylation	down-regulates	0.289	As a consequence, CDK8 overexpression promoted p27 degradation, whereas CDK8 knockdown reduced it.\|We also show that CDK8 promotes phosphorylation of p27 at T187 and then induces p27 ubiquitination and degradation in a Skp2-dependent manner.	SIGNOR-278513
P15056	Q9Y243	phosphorylation	down-regulates	0.289	We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity.	SIGNOR-78693
P35222	Q13554	phosphorylation	down-regulates	0.289	Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552.	SIGNOR-202833
P04049	P53350	phosphorylation	up-regulates activity	0.289	An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).\|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.	SIGNOR-278190
P11831	Q09013	phosphorylation	up-regulates	0.289	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. \| Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.	SIGNOR-236982
O95863	Q9UNE7	ubiquitination	down-regulates quantity by destabilization	0.289	These results indicate that CHIP can ubiquitylate and degrade Snail in a GSK\u20103\u03b2\u2010independent manner.\|These results suggest that CHIP negatively regulates the stability of Snail through inducing its proteasomal degradation.	SIGNOR-278545
P60484	P29375	transcriptional regulation	down-regulates quantity by destabilization	0.289	The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL.	SIGNOR-260079
P26678	P31749	phosphorylation	down-regulates activity	0.289	Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17).	SIGNOR-252578
O95837	O60755	binding	up-regulates activity	0.289	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-257206
P52630	P49841	phosphorylation	down-regulates quantity by destabilization	0.289	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276764
P63096	P21918	binding	up-regulates activity	0.289	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-257043
P37231	P14373	ubiquitination	down-regulates quantity by destabilization	0.289	Mechanically, TRIM27 ubiquitinates and degrades PPARgamma, following induces cleaved Caspase-3 and IL-1beta expression.	SIGNOR-278734
P19086	P25103	binding	up-regulates activity	0.289	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-257316
Q14934	P27361	phosphorylation	up-regulates	0.289	The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity.	SIGNOR-133276
P38405	P41968	binding	up-regulates activity	0.289	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-256748
P04626	P23470	dephosphorylation	up-regulates activity	0.289	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254701
P11233	P62714	dephosphorylation	down-regulates	0.289	Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function	SIGNOR-155349
P04792	P31751	phosphorylation	down-regulates	0.289	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186776
P61160	P18075	binding	up-regulates	0.289	The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2	SIGNOR-144144
P42858	Q9UHD2	phosphorylation	up-regulates activity	0.289	Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity.	SIGNOR-270350
P04264	Q03405	binding	up-regulates activity	0.288	Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.	SIGNOR-251880
P30411	P32298	phosphorylation	down-regulates activity	0.288	Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization.	SIGNOR-251193
P30411	P43250	phosphorylation	down-regulates activity	0.288	Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251207
O75581	Q9Y6M4	phosphorylation	up-regulates activity	0.288	Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493	SIGNOR-275401
O60716	P49674	phosphorylation	down-regulates	0.288	Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex.	SIGNOR-24443
O14936	Q00535	phosphorylation	up-regulates activity	0.288	Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.\|We found that Cdk5 phosphorylates and regulates CASK distribution to membranes.	SIGNOR-280216
Q92974	P63172	binding	down-regulates activity	0.288	Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules.	SIGNOR-277369
Q05586	Q8TBB1	ubiquitination	down-regulates quantity by destabilization	0.288	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272901
Q01167	P57073	transcriptional regulation	up-regulates quantity by expression	0.288	We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.. Our results showed that SOX8 targets FOXK1, thereby regulating its transcription, which has significant impacts on senescence, glycolysis and chemoresistance in ovarian cancer.	SIGNOR-273613
O60879	Q96GD4	phosphorylation	up-regulates	0.288	The microtubule binding fh2 domain of mdia3 is phosphorylated by aurora b kinase in vitro, and cells expressing the nonphosphorylatable mdia3 mutant cannot position chromosomes at the metaphase plate	SIGNOR-172803
P31146	Q00535	phosphorylation	up-regulates activity	0.288	We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway.	SIGNOR-245187
P46531	Q92630	phosphorylation	down-regulates quantity by destabilization	0.288	We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism.	SIGNOR-279035
P28329	Q05513	phosphorylation	up-regulates	0.288	Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity.	SIGNOR-129340
P00533	Q9HD43	dephosphorylation	down-regulates activity	0.288	We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling.	SIGNOR-277090
P60953	P52306	binding	up-regulates	0.288	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171412
Q6PKG0	P31749	phosphorylation	down-regulates activity	0.288	LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1\|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation.	SIGNOR-260992
P49841	Q96RG2	phosphorylation	down-regulates activity	0.288	In vitro, PASK directly phosphorylates GSK3\u03b2 on its inactivating phosphorylation site Ser(9).\|We conclude that PASK phosphorylates and inactivates GSK3\u03b2, thereby preventing PDX-1 serine phosphorylation and alleviating GSK3\u03b2-mediated PDX-1 protein degradation in pancreatic \u03b2-cells.	SIGNOR-279639
O43829	Q96RE7	binding	up-regulates activity	0.288	NAC1 potentiated ZF5 mediated repression in Gal4-DBD fusion transient assays. GST pulldown assays further confirmed proteinprotein interactions between these proteins and NAC1.	SIGNOR-226443
P30679	O43603	binding	up-regulates activity	0.288	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-257226
Q99683	P30307	dephosphorylation	down-regulates activity	0.288	At the interval CDC25C inhibits ASK1, dephosphorylating pThr838 in its activation loop.\|CDC25C dephosphorylates ASK1 to inhibit its activity during the interphase.	SIGNOR-277100
Q15831	Q15418	phosphorylation	down-regulates activity	0.288	Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK.	SIGNOR-209871
Q8WWK9	P06493	phosphorylation	up-regulates	0.288	Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis.	SIGNOR-185317
Q13144	Q92837	binding	up-regulates activity	0.288	In contrast to the GS‐1 peptide, glycogen synthase and the eIF2B peptide, the GSK3‐catalysed phosphorylation of Tau was completely inhibited by FRATtide\|This prevents GSK3 from phosphorylating and inhibiting glycogen synthase [2, 3] and protein synthesis initiation factor eIF2B	SIGNOR-262835
P15336	Q02156	phosphorylation	up-regulates	0.288	Pkc_ phosphorylation of atf2 on thr52. Pkc_ promotes oncogenic functions of atf2 in the nucleus while blocking its apoptotic function at mitochondria	SIGNOR-195761
Q9NRD5	Q6ZN44	binding	up-regulates activity	0.288	Recently, our laboratory showed that UNC5A is coimmunoprecipitated with PICK1 and PKCα. Moreover, we demonstrated that the association of PKCα with UNC5A depends on the activation of PKCα and the ability of UNC5A to bind PICK1	SIGNOR-268181
Q9UI33	Q96PU5	ubiquitination	down-regulates quantity by destabilization	0.288	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253462
P35222	Q9H251	binding	up-regulates activity	0.288	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265861
P00390	Q13131	phosphorylation	up-regulates activity	0.288	Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity.	SIGNOR-273734
Q96PX1	P24941	phosphorylation	up-regulates activity	0.287	CDK2 promotes phosphorylation of RNF157 at the same Ser 660-663 residues that become phosphorylated downstream of combined PI3K and MAPK pathway activity.	SIGNOR-279016
P36956	P06493	phosphorylation	up-regulates	0.287	Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis.	SIGNOR-148354
P05976	P27361	phosphorylation	up-regulates	0.287	Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein.	SIGNOR-148002
P48735	P24752	acetylation	down-regulates activity	0.287	Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2\|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers	SIGNOR-267627
O43524	Q96KS0	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
Q9ULU4	P25440	relocalization	up-regulates activity	0.287	ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.\|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading.	SIGNOR-262036
O60674	P23470	dephosphorylation	down-regulates activity	0.287	Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG.	SIGNOR-254690
Q92985	P63279	sumoylation	down-regulates activity	0.287	One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452.	SIGNOR-266837
P46531	O00629	relocalization	up-regulates	0.287	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-165314
Q9GZM8	P28482	phosphorylation	up-regulates activity	0.287	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274076
Q00613	Q02750	phosphorylation	up-regulates activity	0.287	This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.\|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4).	SIGNOR-279208
P18564	O14713	binding	down-regulates activity	0.287	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257662
P26010	O14713	binding	down-regulates activity	0.287	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257664
P12830	P56524	transcriptional regulation	down-regulates quantity by repression	0.287	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells.	SIGNOR-275663
P05067	P53355	phosphorylation	up-regulates quantity	0.287	DAPK1, but not its kinase deficient mutant (K42A), significantly increased human AŒ≤ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased AŒ≤ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of AŒ≤.\|Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Abeta.	SIGNOR-279518
Q13568	P42229	transcriptional regulation	up-regulates quantity by expression	0.287	The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5	SIGNOR-249508
P36406	O14920	phosphorylation	down-regulates activity	0.287	Phosphorylation of ARD1 by IKKbeta reduced its growth suppression effect.	SIGNOR-279337
P29350	P24941	phosphorylation	down-regulates quantity by destabilization	0.287	Interaction between SHP-1 and Cdk2 was confirmed by co-immunoprecipitations whereby co-precipitated Cdk2 phosphorylated SHP-1 protein.	SIGNOR-279147
P10721	O96017	phosphorylation	up-regulates	0.286	In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk.	SIGNOR-197281
P04637	P62140	dephosphorylation	down-regulates activity	0.286	Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities\|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248572
Q9H2S1	Q05086	ubiquitination	up-regulates activity	0.286	UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis.	SIGNOR-278527
P28329	P05771	phosphorylation	up-regulates	0.286	Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity.	SIGNOR-129288
Q6JBY9	P45983	phosphorylation	down-regulates activity	0.286	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263085
P25490	P68400	phosphorylation	up-regulates	0.286	More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis	SIGNOR-200083
P55957	P19784	phosphorylation	up-regulates activity	0.286	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250978
P55957	P67870	phosphorylation	up-regulates activity	0.286	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-251054
P08235	P28482	phosphorylation	down-regulates quantity by destabilization	0.286	Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276101
O95983	O14965	phosphorylation	up-regulates	0.286	These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3	SIGNOR-93693
P04792	Q9Y243	phosphorylation	down-regulates	0.286	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186780
Q8WYL5	O94806	phosphorylation	down-regulates activity	0.286	Active PKD Isoforms Phosphorylate and Inactivate SSH1L\|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase	SIGNOR-275938
Q13683	P15172	transcriptional regulation	up-regulates quantity by expression	0.286	Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.	SIGNOR-241518
P55957	P48729	phosphorylation	up-regulates activity	0.286	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250785
P24844	Q05397	phosphorylation	up-regulates activity	0.286	It indicates that FAK positively regulates the phosphorylation of MLC2.	SIGNOR-280098
P62140	Q96C90	binding	down-regulates activity	0.286	We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.\|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin	SIGNOR-265743
P04637	Q9UEE5	phosphorylation	up-regulates	0.286	Genetic and biochemical studies have shown that ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed dna-dependent p53 acetylation and b-cell tumor suppression. a cell-free ser20 phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser20 kinases.	SIGNOR-153532
P22415	P49841	phosphorylation	up-regulates activity	0.286	Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186.	SIGNOR-276355
P50148	P34998	binding	up-regulates activity	0.286	Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3	SIGNOR-268619
P31269	O43189	transcriptional regulation	down-regulates quantity by repression	0.286	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260069
P15172	P00519	phosphorylation	down-regulates activity	0.286	We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage.	SIGNOR-253055
Q86VP3	Q13489	polyubiquitination	down-regulates quantity by destabilization	0.286	Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.	SIGNOR-272852

Q96PY6

Q9UKI8

0

phosphorylation

up-regulates activity

0.29

TLK1 phosphorylated NEK1 at T141, which lies in the kinase domain, and caused an increase in its activity.

SIGNOR-275840

P05204

P51812

0

phosphorylation

down-regulates activity

0.29

We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.

SIGNOR-249102

Q9Y2J4

Q9H0M0

0

ubiquitination

up-regulates activity

0.29

AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408.

SIGNOR-271873

P46527

P36888

0

phosphorylation

down-regulates activity

0.29

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

SIGNOR-269208

Q5JVS0

P05771

0

phosphorylation

down-regulates activity

0.29

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249247

P05204

P17252

0

phosphorylation

down-regulates

0.29

Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.

SIGNOR-76320

Q96P20

P07948

0

phosphorylation

down-regulates

0.29

Lyn phosphorylates NLRP3 at Tyr 918 and controls NLRP3 ubiquitination.|Therefore, our data collectively indicate that Lyn inhibits the NLRP3 inflammasome in vivo.

SIGNOR-278485

Q92974

P27361

0

phosphorylation

up-regulates

0.29

Activates rhoa and as a result regulates actin assembly.

SIGNOR-160420

P13611

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.29

By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53.

SIGNOR-255441

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

P46531

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.29

As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1

SIGNOR-264675

Q8TD08

P67775

0

dephosphorylation

down-regulates

0.289

Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%

SIGNOR-142977

P46527

P49336

0

phosphorylation

down-regulates

0.289

As a consequence, CDK8 overexpression promoted p27 degradation, whereas CDK8 knockdown reduced it.|We also show that CDK8 promotes phosphorylation of p27 at T187 and then induces p27 ubiquitination and degradation in a Skp2-dependent manner.

SIGNOR-278513

P15056

Q9Y243

0

phosphorylation

down-regulates

0.289

We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity.

SIGNOR-78693

P35222

Q13554

0

phosphorylation

down-regulates

0.289

Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552.

SIGNOR-202833

P04049

P53350

0

phosphorylation

up-regulates activity

0.289

An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.

SIGNOR-278190

P11831

Q09013

0

phosphorylation

up-regulates

0.289

Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.

SIGNOR-236982

O95863

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.289

These results indicate that CHIP can ubiquitylate and degrade Snail in a GSK\u20103\u03b2\u2010independent manner.|These results suggest that CHIP negatively regulates the stability of Snail through inducing its proteasomal degradation.

SIGNOR-278545

P60484

P29375

0

transcriptional regulation

down-regulates quantity by destabilization

0.289

The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL.

SIGNOR-260079

P26678

P31749

0

phosphorylation

down-regulates activity

0.289

Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17).

SIGNOR-252578

O95837

O60755

0

binding

up-regulates activity

0.289

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-257206

P52630

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.289

GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.

SIGNOR-276764

P63096

P21918

0

binding

up-regulates activity

0.289

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-257043

P37231

P14373

0

ubiquitination

down-regulates quantity by destabilization

0.289

Mechanically, TRIM27 ubiquitinates and degrades PPARgamma, following induces cleaved Caspase-3 and IL-1beta expression.

SIGNOR-278734

P19086

P25103

0

binding

up-regulates activity

0.289

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-257316

Q14934

P27361

0

phosphorylation

up-regulates

0.289

The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity.

SIGNOR-133276

P38405

P41968

0

binding

up-regulates activity

0.289

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-256748

P04626

P23470

0

dephosphorylation

up-regulates activity

0.289

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

SIGNOR-254701

P11233

P62714

0

dephosphorylation

down-regulates

0.289

Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function

SIGNOR-155349

P04792

P31751

0

phosphorylation

down-regulates

0.289

First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.

SIGNOR-186776

P61160

P18075

0

binding

up-regulates

0.289

The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2

SIGNOR-144144

P42858

Q9UHD2

0

phosphorylation

up-regulates activity

0.289

Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity.

SIGNOR-270350

P04264

Q03405

0

binding

up-regulates activity

0.288

Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.

SIGNOR-251880

P30411

P32298

0

phosphorylation

down-regulates activity

0.288

Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization.

SIGNOR-251193

P30411

P43250

0

phosphorylation

down-regulates activity

0.288

Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.

SIGNOR-251207

O75581

Q9Y6M4

0

phosphorylation

up-regulates activity

0.288

Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493

SIGNOR-275401

O60716

P49674

0

phosphorylation

down-regulates

0.288

Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex.

SIGNOR-24443

O14936

Q00535

0

phosphorylation

up-regulates activity

0.288

Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.|We found that Cdk5 phosphorylates and regulates CASK distribution to membranes.

SIGNOR-280216

Q92974

P63172

0

binding

down-regulates activity

0.288

Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules.

SIGNOR-277369

Q05586

Q8TBB1

0

ubiquitination

down-regulates quantity by destabilization

0.288

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

SIGNOR-272901

Q01167

P57073

0

transcriptional regulation

up-regulates quantity by expression

0.288

We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.. Our results showed that SOX8 targets FOXK1, thereby regulating its transcription, which has significant impacts on senescence, glycolysis and chemoresistance in ovarian cancer.

SIGNOR-273613

O60879

Q96GD4

0

phosphorylation

up-regulates

0.288

The microtubule binding fh2 domain of mdia3 is phosphorylated by aurora b kinase in vitro, and cells expressing the nonphosphorylatable mdia3 mutant cannot position chromosomes at the metaphase plate

SIGNOR-172803

P31146

Q00535

0

phosphorylation

up-regulates activity

0.288

We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway.

SIGNOR-245187

P46531

Q92630

0

phosphorylation

down-regulates quantity by destabilization

0.288

We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism.

SIGNOR-279035

P28329

Q05513

0

phosphorylation

up-regulates

0.288

Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity.

SIGNOR-129340

P00533

Q9HD43

0

dephosphorylation

down-regulates activity

0.288

We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling.

SIGNOR-277090

P60953

P52306

0

binding

up-regulates

0.288

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

SIGNOR-171412

Q6PKG0

P31749

0

phosphorylation

down-regulates activity

0.288

LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation.

SIGNOR-260992

P49841

Q96RG2

0

phosphorylation

down-regulates activity

0.288

In vitro, PASK directly phosphorylates GSK3\u03b2 on its inactivating phosphorylation site Ser(9).|We conclude that PASK phosphorylates and inactivates GSK3\u03b2, thereby preventing PDX-1 serine phosphorylation and alleviating GSK3\u03b2-mediated PDX-1 protein degradation in pancreatic \u03b2-cells.

SIGNOR-279639

O43829

Q96RE7

0

binding

up-regulates activity

0.288

NAC1 potentiated ZF5 mediated repression in Gal4-DBD fusion transient assays. GST pulldown assays further confirmed proteinprotein interactions between these proteins and NAC1.

SIGNOR-226443

P30679

O43603

0

binding

up-regulates activity

0.288

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-257226

Q99683

P30307

0

dephosphorylation

down-regulates activity

0.288

At the interval CDC25C inhibits ASK1, dephosphorylating pThr838 in its activation loop.|CDC25C dephosphorylates ASK1 to inhibit its activity during the interphase.

SIGNOR-277100

Q15831

Q15418

0

phosphorylation

down-regulates activity

0.288

Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK.

SIGNOR-209871

Q8WWK9

P06493

0

phosphorylation

up-regulates

0.288

Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis.

SIGNOR-185317

Q13144

Q92837

0

binding

up-regulates activity

0.288

In contrast to the GS‐1 peptide, glycogen synthase and the eIF2B peptide, the GSK3‐catalysed phosphorylation of Tau was completely inhibited by FRATtide|This prevents GSK3 from phosphorylating and inhibiting glycogen synthase [2, 3] and protein synthesis initiation factor eIF2B

SIGNOR-262835

P15336

Q02156

0

phosphorylation

up-regulates

0.288

Pkc_ phosphorylation of atf2 on thr52. Pkc_ promotes oncogenic functions of atf2 in the nucleus while blocking its apoptotic function at mitochondria

SIGNOR-195761

Q9NRD5

Q6ZN44

0

binding

up-regulates activity

0.288

Recently, our laboratory showed that UNC5A is coimmunoprecipitated with PICK1 and PKCα. Moreover, we demonstrated that the association of PKCα with UNC5A depends on the activation of PKCα and the ability of UNC5A to bind PICK1

SIGNOR-268181

Q9UI33

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.288

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253462

P35222

Q9H251

0

binding

up-regulates activity

0.288

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265861

P00390

Q13131

0

phosphorylation

up-regulates activity

0.288

Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity.

SIGNOR-273734

Q96PX1

P24941

0

phosphorylation

up-regulates activity

0.287

CDK2 promotes phosphorylation of RNF157 at the same Ser 660-663 residues that become phosphorylated downstream of combined PI3K and MAPK pathway activity.

SIGNOR-279016

P36956

P06493

0

phosphorylation

up-regulates

0.287

Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis.

SIGNOR-148354

P05976

P27361

0

phosphorylation

up-regulates

0.287

Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein.

SIGNOR-148002

P48735

P24752

0

acetylation

down-regulates activity

0.287

Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers

SIGNOR-267627

O43524

Q96KS0

0

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

Q9ULU4

P25440

0

relocalization

up-regulates activity

0.287

ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading.

SIGNOR-262036

O60674

P23470

0

dephosphorylation

down-regulates activity

0.287

Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG.

SIGNOR-254690

Q92985

P63279

0

sumoylation

down-regulates activity

0.287

One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452.

SIGNOR-266837

P46531

O00629

0

relocalization

up-regulates

0.287

Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.

SIGNOR-165314

Q9GZM8

P28482

0

phosphorylation

up-regulates activity

0.287

In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites

SIGNOR-274076

Q00613

Q02750

0

phosphorylation

up-regulates activity

0.287

This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4).

SIGNOR-279208

P18564

O14713

0

binding

down-regulates activity

0.287

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

SIGNOR-257662

P26010

O14713

0

binding

down-regulates activity

0.287

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

SIGNOR-257664

P12830

P56524

0

transcriptional regulation

down-regulates quantity by repression

0.287

GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells.

SIGNOR-275663

P05067

P53355

0

phosphorylation

up-regulates quantity

0.287

DAPK1, but not its kinase deficient mutant (K42A), significantly increased human AŒ≤ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased AŒ≤ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of AŒ≤.|Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Abeta.

SIGNOR-279518

Q13568

P42229

0

transcriptional regulation

up-regulates quantity by expression

0.287

The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5

SIGNOR-249508

P36406

O14920

0

phosphorylation

down-regulates activity

0.287

Phosphorylation of ARD1 by IKKbeta reduced its growth suppression effect.

SIGNOR-279337

P29350

P24941

0

phosphorylation

down-regulates quantity by destabilization

0.287

Interaction between SHP-1 and Cdk2 was confirmed by co-immunoprecipitations whereby co-precipitated Cdk2 phosphorylated SHP-1 protein.

SIGNOR-279147

P10721

O96017

0

phosphorylation

up-regulates

0.286

In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk.

SIGNOR-197281

P04637

P62140

0

dephosphorylation

down-regulates activity

0.286

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

SIGNOR-248572

Q9H2S1

Q05086

0

ubiquitination

up-regulates activity

0.286

UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis.

SIGNOR-278527

P28329

P05771

0

phosphorylation

up-regulates

0.286

Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity.

SIGNOR-129288

Q6JBY9

P45983

0

phosphorylation

down-regulates activity

0.286

CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263085

P25490

P68400

0

phosphorylation

up-regulates

0.286

More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis

SIGNOR-200083

P55957

P19784

0

phosphorylation

up-regulates activity

0.286

Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.

SIGNOR-250978

P55957

P67870

0

phosphorylation

up-regulates activity

0.286

Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.

SIGNOR-251054

P08235

P28482

0

phosphorylation

down-regulates quantity by destabilization

0.286

Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.

SIGNOR-276101

O95983

O14965

0

phosphorylation

up-regulates

0.286

These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3

SIGNOR-93693

P04792

Q9Y243

0

phosphorylation

down-regulates

0.286

First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.

SIGNOR-186780

Q8WYL5

O94806

0

phosphorylation

down-regulates activity

0.286

Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase

SIGNOR-275938

Q13683

P15172

0

transcriptional regulation

up-regulates quantity by expression

0.286

Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.

SIGNOR-241518

P55957

P48729

0

phosphorylation

up-regulates activity

0.286

Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.

SIGNOR-250785

P24844

Q05397

0

phosphorylation

up-regulates activity

0.286

It indicates that FAK positively regulates the phosphorylation of MLC2.

SIGNOR-280098

P62140

Q96C90

0

binding

down-regulates activity

0.286

We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin

SIGNOR-265743

P04637

Q9UEE5

0

phosphorylation

up-regulates

0.286

Genetic and biochemical studies have shown that ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed dna-dependent p53 acetylation and b-cell tumor suppression. a cell-free ser20 phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser20 kinases.

SIGNOR-153532

P22415

P49841

0

phosphorylation

up-regulates activity

0.286

Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186.

SIGNOR-276355

P50148

P34998

0

binding

up-regulates activity

0.286

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

SIGNOR-268619

P31269

O43189

0

transcriptional regulation

down-regulates quantity by repression

0.286

These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.

SIGNOR-260069

P15172

P00519

0

phosphorylation

down-regulates activity

0.286

We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage.

SIGNOR-253055

Q86VP3

Q13489

0

polyubiquitination

down-regulates quantity by destabilization

0.286

Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.

SIGNOR-272852