GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P62714	Q13315	1	dephosphorylation	down-regulates activity	0.269	Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.	SIGNOR-248601
P52564	P53779	1	phosphorylation	up-regulates	0.464	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)	SIGNOR-45363
P00533	Q13237	0	phosphorylation	down-regulates activity	0.2	Recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells.	SIGNOR-277589
P33991	P06493	0	phosphorylation	down-regulates activity	0.592	We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex.	SIGNOR-100877
P50613	P10276	1	phosphorylation	up-regulates	0.546	However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant.	SIGNOR-49693
P17612	Q7KZI7	1	phosphorylation	down-regulates activity	0.2	Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.	SIGNOR-276870
Q92529	P04626	0	relocalization	up-regulates	0.549	Erbb3 is characterized by a large number of binding sites for phosphatidylinositol-3-kinase (pi3k), while erbb2 has only few interaction partners with shc as the most frequent one.	SIGNOR-146855
Q14571	Q13557	0	phosphorylation	down-regulates activity	0.308	Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability.	SIGNOR-262692
Q13627	Q9NYY3	1	phosphorylation	up-regulates quantity by stabilization	0.313	In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.	SIGNOR-277805
O60341	Q16665	0	transcriptional regulation	down-regulates quantity by repression	0.265	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271573
P52630	Q92793	0	acetylation	up-regulates activity	0.557	STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation.	SIGNOR-217891
O96006	P46783	1	transcriptional regulation	up-regulates quantity by expression	0.2	HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. \| Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.	SIGNOR-266083
Q9ULU4	P03956	1	transcriptional regulation	down-regulates quantity by repression	0.2	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262042
P60953	Q58EX7	0	guanine nucleotide exchange factor	up-regulates activity	0.36	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260564
Q8IWR1	Q00535	0	phosphorylation	up-regulates activity	0.2	Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation.	SIGNOR-272929
P11362	P18669	1	phosphorylation	up-regulates activity	0.33	Nevertheless, these data suggest that FGFR1 dependent tyrosine phosphorylation " further " enhances PGAM1 activation.\|Phosphorylation of PGAM1 WT by FGFR1 resulted in a significant increase in the amount of bound 2,3-BPG analogue, whereas substitution of PGAM1 Y26 abolished enhanced binding of cofactor in the presence of rFGFR1 (XREF_FIG).	SIGNOR-279175
P09874	P24941	0	phosphorylation	up-regulates activity	0.358	CDK2 dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells.\|Hormone dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities.	SIGNOR-279146
P68400	Q8N163	1	phosphorylation	up-regulates activity	0.2	CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. \|In our results, CK2alpha affected the\|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1	SIGNOR-267666
P17861-2	P18850	0	transcriptional regulation	up-regulates quantity by expression	0.654	Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network	SIGNOR-260184
P01106	O75626	0	transcriptional regulation	down-regulates quantity by repression	0.436	The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b	SIGNOR-99119
Q92542	O00141	0	phosphorylation	down-regulates quantity	0.337	Furthermore, SGK1 directly bound to and phosphorylated Nicastrin on Ser437, thereby promoting protein degradation.\|We showed that SGK1 downregulates Nicastrin protein levels.	SIGNOR-280122
O60674	P03372	1	phosphorylation	down-regulates quantity	0.435	From these results, it can be concluded that JAK2 negatively regulates ERalpha protein level.We next analyzed by which mechanisms JAK2 could regulate ERalpha protein level.\|We investigated whether JAK2 phosphorylates ER\u03b1 resulting in its ubiquitination and proteasomal degradation.	SIGNOR-278949
P42684	P07203	1	phosphorylation	up-regulates activity	0.322	GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.	SIGNOR-104328
Q13536	P01100	1	transcriptional regulation	up-regulates quantity by expression	0.2	CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types.	SIGNOR-261569
P43405	P06239	1	phosphorylation	down-regulates activity	0.592	Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling	SIGNOR-246562
P31751	P04792	1	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
P29350	P00519	0	phosphorylation	up-regulates activity	0.414	The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-260820
Q15418	Q9UBP6	1	phosphorylation	down-regulates	0.324	Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro.	SIGNOR-135948
O14827	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.553	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260573
P68400	Q9BXW9	1	phosphorylation	down-regulates activity	0.2	Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.	SIGNOR-276730
Q9BYW2	P68431	1	trimethylation	up-regulates activity	0.2	Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD.	SIGNOR-269071
Q04760	P21802	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276184
P09651	P31749	0	phosphorylation	down-regulates	0.412	Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.	SIGNOR-252519
P00519	P17844	1	phosphorylation	up-regulates	0.357	These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway.	SIGNOR-149988
P50613	O95243	1	phosphorylation	down-regulates activity	0.2	The mechanistic basis for the phase-separation of MED1 is not well understood, and we hypothesize that this may be due to the phosphorylation of MED1 by CDK7 in response to growth stimuli or nuclear translocation of steroid hormone receptors, such as AR.\|Together, we demonstrate that CDK7 inhibition selectively targets MED1 mediated, AR dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC.	SIGNOR-279686
Q9UGI0	P31749	0	phosphorylation	up-regulates activity	0.2	Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination.	SIGNOR-273484
P68400	P35226	1	phosphorylation	down-regulates quantity by destabilization	0.269	Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function.	SIGNOR-277345
P28482	P38936	1	phosphorylation	down-regulates quantity by destabilization	0.364	Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.\|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130.	SIGNOR-185215
P17252	Q01970	1	phosphorylation	down-regulates	0.481	These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity.	SIGNOR-58859
Q92918	P07948	0	phosphorylation	up-regulates activity	0.381	BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain.	SIGNOR-251403
Q05195	P31749	0	phosphorylation	down-regulates	0.363	Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1.	SIGNOR-252525
P17612	O14921	1	phosphorylation	up-regulates quantity by stabilization	0.334	Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry.	SIGNOR-259835
Q12879	P54829	0	dephosphorylation	down-regulates activity	0.432	STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).\|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP.	SIGNOR-277089
P17676	P98066	1	transcriptional regulation	up-regulates quantity by expression	0.302	In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells.	SIGNOR-254055
O14965	Q14863	1	phosphorylation	down-regulates activity	0.2	Here, we report that Aurora kinase A phosphorylates mPOU at Ser197 and inhibit its DNA-binding ability.	SIGNOR-273546
P27361	P23443	1	phosphorylation	up-regulates activity	0.607	Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats	SIGNOR-134662
P38398	P62136	0	dephosphorylation	down-regulates activity	0.377	Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. \|Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524.	SIGNOR-248560
Q8NHY2	Q13085	1	ubiquitination	down-regulates quantity by destabilization	0.2	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271598
P35568	Q06124	0	dephosphorylation	down-regulates	0.897	The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.	SIGNOR-74856
P61254	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.498	In addition, Mdm2 ubiquitylates L26, leading to its proteasome-mediated degradation.\|We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26.	SIGNOR-278828
Q92558	P12931	0	phosphorylation	up-regulates	0.407	The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex	SIGNOR-142724
O43524	P45983	0	phosphorylation	up-regulates activity	0.65	As JNK1 phosphorylates FOXO3 at S574, 12 allowing formation of the proapoptotic species, we tested whether FOXO3 acetylation is required for the JNK1-FOXO3 interaction.	SIGNOR-280030
Q05519	Q14114	1	post transcriptional regulation	up-regulates quantity by stabilization	0.2	We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling.	SIGNOR-269670
Q13671	Q15139	0	phosphorylation	down-regulates	0.402	Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation.	SIGNOR-113960
Q01484	O94856	0	relocalization	up-regulates quantity	0.694	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266716
P35568	P53350	0	phosphorylation	down-regulates activity	0.267	Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase\| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin.	SIGNOR-135688
Q9UHD2	P42226	1	phosphorylation	up-regulates	0.674	We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing.	SIGNOR-176775
Q96JA1	P04626	1	ubiquitination	down-regulates	0.403	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139948
Q96GD0	Q00987	1	dephosphorylation	down-regulates activity	0.2	Considering the roles of NF2 in actin dynamics and Mdm2 regulation - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.\|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38.	SIGNOR-277151
Q14643	P17612	0	phosphorylation	down-regulates activity	0.556	IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site.	SIGNOR-249996
Q6P1M3	P41743	0	phosphorylation	up-regulates activity	0.687	This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.	SIGNOR-263180
P42345	Q13542	1	phosphorylation	down-regulates	0.661	Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2).	SIGNOR-122014
Q96T58	Q13153	0	phosphorylation	down-regulates activity	0.2	Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and Thr3568 within the SHARP repression domain.	SIGNOR-278968
P17612	P17752	1	phosphorylation	up-regulates activity	0.35	The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme.	SIGNOR-250062
O15553	Q16512	0	phosphorylation	down-regulates activity	0.384	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome.	SIGNOR-275461
P12931	Q01196	1	phosphorylation	up-regulates activity	0.412	Src phosphorylates Runx1 on one central and four C-terminal tyrosines.\|We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter.	SIGNOR-279656
Q09472	O75116	0	phosphorylation	up-regulates activity	0.297	Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.\|p300 acetyltransferase activity is dependent on its phosphorylation status in cells, and p300 phosphorylation by ROCK2 results in an increase in its acetyltransferase activity in vitro.	SIGNOR-279482
Q02750	Q13153	0	phosphorylation	up-regulates activity	0.582	We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation.	SIGNOR-236002
P68400	P17936	1	phosphorylation	up-regulates quantity by stabilization	0.338	The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro \| These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.	SIGNOR-250903
Q05513	P35568	1	phosphorylation	down-regulates activity	0.723	Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results.	SIGNOR-236760
Q02156	P61764	1	phosphorylation	down-regulates quantity	0.273	These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.\|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.	SIGNOR-279479
Q13118	Q15582	1	transcriptional regulation	up-regulates quantity by expression	0.242	Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia.	SIGNOR-253212
P23528	Q13418	0	phosphorylation	down-regulates	0.35	Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells.	SIGNOR-160756
P43629	P05129	0	phosphorylation	down-regulates	0.2	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158133
P24941	Q99626	1	phosphorylation	down-regulates quantity by destabilization	0.476	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation\|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.	SIGNOR-250729
P06493	Q96EB6	1	phosphorylation	up-regulates	0.528	We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells	SIGNOR-182863
P15056	P68104	1	phosphorylation	down-regulates quantity by destabilization	0.262	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.	SIGNOR-276404
Q8N3U4	Q9NP77	0	dephosphorylation	up-regulates activity	0.298	Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution.\|anti‐phospho SA2 serine 1224	SIGNOR-275531
Q9NR80	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.739	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260532
P08047	P15172	0	transcriptional regulation	down-regulates quantity by repression	0.373	These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport.	SIGNOR-241765
Q13976	Q9Y613	1	phosphorylation	up-regulates	0.354	Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization	SIGNOR-123646
Q13464	O14649	1	phosphorylation	down-regulates	0.2	Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway.	SIGNOR-176025
P27361	P29590	1	phosphorylation	up-regulates	0.339	Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis.	SIGNOR-124317
Q15910	Q14680	0	phosphorylation	up-regulates quantity by stabilization	0.329	We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.	SIGNOR-277480
P54646	O60825	1	phosphorylation	up-regulates activity	0.443	AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. activation of PFK-2 was due to the phosphorylation of Ser466	SIGNOR-250323
O95817	Q00535	0	phosphorylation	down-regulates quantity by destabilization	0.2	CDK5-mediated phosphorylation on S297 promotes BAG3 degradation.	SIGNOR-277502
O15393	P0DTC2	1	cleavage	up-regulates activity	0.2	Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells	SIGNOR-260736
Q14344	P17612	0	phosphorylation	down-regulates activity	0.366	PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203).	SIGNOR-249985
Q13535	Q9BXW9	1	phosphorylation	up-regulates	0.673	In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents	SIGNOR-149305
Q01196	P12931	0	phosphorylation	up-regulates activity	0.412	Src phosphorylates Runx1 on one central and four C-terminal tyrosines.\|We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter.	SIGNOR-279656
P15172	Q7Z6Z7	0	ubiquitination	down-regulates quantity	0.343	Importantly, addition of WT HUWE1 to a proteolytic reaction mixture enhanced the degradation of MyoD.\|Mass-spectrometry analyses show that HUWE1 can ubiquitinate MyoD at its N-terminal residue, though the preferred sites are - at least in a cell free system - the internal lysines of the protein.	SIGNOR-278694
Q13315	Q9HB75	1	phosphorylation	up-regulates activity	0.636	ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury.	SIGNOR-262640
Q13131	Q8NE86	1	phosphorylation	up-regulates activity	0.2	Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). \|In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57	SIGNOR-275547
Q13555	Q14524	1	phosphorylation	up-regulates activity	0.291	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).\|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. \| Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275779
Q9Y2X9	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression\|	SIGNOR-264890
P17612	P13612	1	phosphorylation	up-regulates activity	0.494	PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading	SIGNOR-110119
P24723	P04083	1	phosphorylation	up-regulates	0.2	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202792
P08670	Q13177	0	phosphorylation	down-regulates activity	0.307	In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.	SIGNOR-250243
Q8TF68	P03956	1	transcriptional regulation	up-regulates quantity by expression	0.307	Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence.	SIGNOR-266229
Q02156	P15336	1	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

P62714

Q13315

1

dephosphorylation

down-regulates activity

0.269

Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.

SIGNOR-248601

P52564

P53779

1

phosphorylation

up-regulates

0.464

A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)

SIGNOR-45363

P00533

Q13237

0

phosphorylation

down-regulates activity

0.2

Recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells.

SIGNOR-277589

P33991

P06493

0

phosphorylation

down-regulates activity

0.592

We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex.

SIGNOR-100877

P50613

P10276

1

phosphorylation

up-regulates

0.546

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

SIGNOR-49693

P17612

Q7KZI7

1

phosphorylation

down-regulates activity

0.2

Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.

SIGNOR-276870

Q92529

P04626

0

relocalization

up-regulates

0.549

Erbb3 is characterized by a large number of binding sites for phosphatidylinositol-3-kinase (pi3k), while erbb2 has only few interaction partners with shc as the most frequent one.

SIGNOR-146855

Q14571

Q13557

0

phosphorylation

down-regulates activity

0.308

Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability.

SIGNOR-262692

Q13627

Q9NYY3

1

phosphorylation

up-regulates quantity by stabilization

0.313

In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.

SIGNOR-277805

O60341

Q16665

0

transcriptional regulation

down-regulates quantity by repression

0.265

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271573

P52630

Q92793

0

acetylation

up-regulates activity

0.557

STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation.

SIGNOR-217891

O96006

P46783

1

transcriptional regulation

up-regulates quantity by expression

0.2

HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.

SIGNOR-266083

Q9ULU4

P03956

1

transcriptional regulation

down-regulates quantity by repression

0.2

Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported

SIGNOR-262042

P60953

Q58EX7

0

guanine nucleotide exchange factor

up-regulates activity

0.36

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

SIGNOR-260564

Q8IWR1

Q00535

0

phosphorylation

up-regulates activity

0.2

Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation.

SIGNOR-272929

P11362

P18669

1

phosphorylation

up-regulates activity

0.33

Nevertheless, these data suggest that FGFR1 dependent tyrosine phosphorylation " further " enhances PGAM1 activation.|Phosphorylation of PGAM1 WT by FGFR1 resulted in a significant increase in the amount of bound 2,3-BPG analogue, whereas substitution of PGAM1 Y26 abolished enhanced binding of cofactor in the presence of rFGFR1 (XREF_FIG).

SIGNOR-279175

P09874

P24941

0

phosphorylation

up-regulates activity

0.358

CDK2 dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells.|Hormone dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities.

SIGNOR-279146

P68400

Q8N163

1

phosphorylation

up-regulates activity

0.2

CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1

SIGNOR-267666

P17861-2

P18850

0

transcriptional regulation

up-regulates quantity by expression

0.654

Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network

SIGNOR-260184

P01106

O75626

0

transcriptional regulation

down-regulates quantity by repression

0.436

The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b

SIGNOR-99119

Q92542

O00141

0

phosphorylation

down-regulates quantity

0.337

Furthermore, SGK1 directly bound to and phosphorylated Nicastrin on Ser437, thereby promoting protein degradation.|We showed that SGK1 downregulates Nicastrin protein levels.

SIGNOR-280122

O60674

P03372

1

phosphorylation

down-regulates quantity

0.435

From these results, it can be concluded that JAK2 negatively regulates ERalpha protein level.We next analyzed by which mechanisms JAK2 could regulate ERalpha protein level.|We investigated whether JAK2 phosphorylates ER\u03b1 resulting in its ubiquitination and proteasomal degradation.

SIGNOR-278949

P42684

P07203

1

phosphorylation

up-regulates activity

0.322

GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.

SIGNOR-104328

Q13536

P01100

1

transcriptional regulation

up-regulates quantity by expression

0.2

CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types.

SIGNOR-261569

P43405

P06239

1

phosphorylation

down-regulates activity

0.592

Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling

SIGNOR-246562

P31751

P04792

1

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

P29350

P00519

0

phosphorylation

up-regulates activity

0.414

The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.

SIGNOR-260820

Q15418

Q9UBP6

1

phosphorylation

down-regulates

0.324

Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro.

SIGNOR-135948

O14827

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.553

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

SIGNOR-260573

P68400

Q9BXW9

1

phosphorylation

down-regulates activity

0.2

Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.

SIGNOR-276730

Q9BYW2

P68431

1

trimethylation

up-regulates activity

0.2

Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD.

SIGNOR-269071

Q04760

P21802

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276184

P09651

P31749

0

phosphorylation

down-regulates

0.412

Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.

SIGNOR-252519

P00519

P17844

1

phosphorylation

up-regulates

0.357

These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway.

SIGNOR-149988

P50613

O95243

1

phosphorylation

down-regulates activity

0.2

The mechanistic basis for the phase-separation of MED1 is not well understood, and we hypothesize that this may be due to the phosphorylation of MED1 by CDK7 in response to growth stimuli or nuclear translocation of steroid hormone receptors, such as AR.|Together, we demonstrate that CDK7 inhibition selectively targets MED1 mediated, AR dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC.

SIGNOR-279686

Q9UGI0

P31749

0

phosphorylation

up-regulates activity

0.2

Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination.

SIGNOR-273484

P68400

P35226

1

phosphorylation

down-regulates quantity by destabilization

0.269

Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function.

SIGNOR-277345

P28482

P38936

1

phosphorylation

down-regulates quantity by destabilization

0.364

Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130.

SIGNOR-185215

P17252

Q01970

1

phosphorylation

down-regulates

0.481

These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity.

SIGNOR-58859

Q92918

P07948

0

phosphorylation

up-regulates activity

0.381

BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain.

SIGNOR-251403

Q05195

P31749

0

phosphorylation

down-regulates

0.363

Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1.

SIGNOR-252525

P17612

O14921

1

phosphorylation

up-regulates quantity by stabilization

0.334

Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry.

SIGNOR-259835

Q12879

P54829

0

dephosphorylation

down-regulates activity

0.432

STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP.

SIGNOR-277089

P17676

P98066

1

transcriptional regulation

up-regulates quantity by expression

0.302

In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells.

SIGNOR-254055

O14965

Q14863

1

phosphorylation

down-regulates activity

0.2

Here, we report that Aurora kinase A phosphorylates mPOU at Ser197 and inhibit its DNA-binding ability.

SIGNOR-273546

P27361

P23443

1

phosphorylation

up-regulates activity

0.607

Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats

SIGNOR-134662

P38398

P62136

0

dephosphorylation

down-regulates activity

0.377

Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524.

SIGNOR-248560

Q8NHY2

Q13085

1

ubiquitination

down-regulates quantity by destabilization

0.2

TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).

SIGNOR-271598

P35568

Q06124

0

dephosphorylation

down-regulates

0.897

The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.

SIGNOR-74856

P61254

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.498

In addition, Mdm2 ubiquitylates L26, leading to its proteasome-mediated degradation.|We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26.

SIGNOR-278828

Q92558

P12931

0

phosphorylation

up-regulates

0.407

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

SIGNOR-142724

O43524

P45983

0

phosphorylation

up-regulates activity

0.65

As JNK1 phosphorylates FOXO3 at S574, 12 allowing formation of the proapoptotic species, we tested whether FOXO3 acetylation is required for the JNK1-FOXO3 interaction.

SIGNOR-280030

Q05519

Q14114

1

post transcriptional regulation

up-regulates quantity by stabilization

0.2

We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling.

SIGNOR-269670

Q13671

Q15139

0

phosphorylation

down-regulates

0.402

Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation.

SIGNOR-113960

Q01484

O94856

0

relocalization

up-regulates quantity

0.694

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266716

P35568

P53350

0

phosphorylation

down-regulates activity

0.267

Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin.

SIGNOR-135688

Q9UHD2

P42226

1

phosphorylation

up-regulates

0.674

We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing.

SIGNOR-176775

Q96JA1

P04626

1

ubiquitination

down-regulates

0.403

We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.

SIGNOR-139948

Q96GD0

Q00987

1

dephosphorylation

down-regulates activity

0.2

Considering the roles of NF2 in actin dynamics and Mdm2 regulation - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38.

SIGNOR-277151

Q14643

P17612

0

phosphorylation

down-regulates activity

0.556

IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site.

SIGNOR-249996

Q6P1M3

P41743

0

phosphorylation

up-regulates activity

0.687

This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.

SIGNOR-263180

P42345

Q13542

1

phosphorylation

down-regulates

0.661

Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2).

SIGNOR-122014

Q96T58

Q13153

0

phosphorylation

down-regulates activity

0.2

Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and Thr3568 within the SHARP repression domain.

SIGNOR-278968

P17612

P17752

1

phosphorylation

up-regulates activity

0.35

The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme.

SIGNOR-250062

O15553

Q16512

0

phosphorylation

down-regulates activity

0.384

PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome.

SIGNOR-275461

P12931

Q01196

1

phosphorylation

up-regulates activity

0.412

Src phosphorylates Runx1 on one central and four C-terminal tyrosines.|We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter.

SIGNOR-279656

Q09472

O75116

0

phosphorylation

up-regulates activity

0.297

Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.|p300 acetyltransferase activity is dependent on its phosphorylation status in cells, and p300 phosphorylation by ROCK2 results in an increase in its acetyltransferase activity in vitro.

SIGNOR-279482

Q02750

Q13153

0

phosphorylation

up-regulates activity

0.582

We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation.

SIGNOR-236002

P68400

P17936

1

phosphorylation

up-regulates quantity by stabilization

0.338

The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.

SIGNOR-250903

Q05513

P35568

1

phosphorylation

down-regulates activity

0.723

Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results.

SIGNOR-236760

Q02156

P61764

1

phosphorylation

down-regulates quantity

0.273

These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.

SIGNOR-279479

Q13118

Q15582

1

transcriptional regulation

up-regulates quantity by expression

0.242

Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia.

SIGNOR-253212

P23528

Q13418

0

phosphorylation

down-regulates

0.35

Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells.

SIGNOR-160756

P43629

P05129

0

phosphorylation

down-regulates

0.2

Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.

SIGNOR-158133

P24941

Q99626

1

phosphorylation

down-regulates quantity by destabilization

0.476

Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.

SIGNOR-250729

P06493

Q96EB6

1

phosphorylation

up-regulates

0.528

We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells

SIGNOR-182863

P15056

P68104

1

phosphorylation

down-regulates quantity by destabilization

0.262

Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.

SIGNOR-276404

Q8N3U4

Q9NP77

0

dephosphorylation

up-regulates activity

0.298

Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution.|anti‐phospho SA2 serine 1224

SIGNOR-275531

Q9NR80

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.739

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

SIGNOR-260532

P08047

P15172

0

transcriptional regulation

down-regulates quantity by repression

0.373

These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport.

SIGNOR-241765

Q13976

Q9Y613

1

phosphorylation

up-regulates

0.354

Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization

SIGNOR-123646

Q13464

O14649

1

phosphorylation

down-regulates

0.2

Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway.

SIGNOR-176025

P27361

P29590

1

phosphorylation

up-regulates

0.339

Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis.

SIGNOR-124317

Q15910

Q14680

0

phosphorylation

up-regulates quantity by stabilization

0.329

We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.

SIGNOR-277480

P54646

O60825

1

phosphorylation

up-regulates activity

0.443

AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. activation of PFK-2 was due to the phosphorylation of Ser466

SIGNOR-250323

O95817

Q00535

0

phosphorylation

down-regulates quantity by destabilization

0.2

CDK5-mediated phosphorylation on S297 promotes BAG3 degradation.

SIGNOR-277502

O15393

P0DTC2

1

cleavage

up-regulates activity

0.2

Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells

SIGNOR-260736

Q14344

P17612

0

phosphorylation

down-regulates activity

0.366

PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203).

SIGNOR-249985

Q13535

Q9BXW9

1

phosphorylation

up-regulates

0.673

In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents

SIGNOR-149305

Q01196

P12931

0

phosphorylation

up-regulates activity

0.412

Src phosphorylates Runx1 on one central and four C-terminal tyrosines.|We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter.

SIGNOR-279656

P15172

Q7Z6Z7

0

ubiquitination

down-regulates quantity

0.343

Importantly, addition of WT HUWE1 to a proteolytic reaction mixture enhanced the degradation of MyoD.|Mass-spectrometry analyses show that HUWE1 can ubiquitinate MyoD at its N-terminal residue, though the preferred sites are - at least in a cell free system - the internal lysines of the protein.

SIGNOR-278694

Q13315

Q9HB75

1

phosphorylation

up-regulates activity

0.636

ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury.

SIGNOR-262640

Q13131

Q8NE86

1

phosphorylation

up-regulates activity

0.2

Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57

SIGNOR-275547

Q13555

Q14524

1

phosphorylation

up-regulates activity

0.291

Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5

SIGNOR-275779

Q9Y2X9

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression|

SIGNOR-264890

P17612

P13612

1

phosphorylation

up-regulates activity

0.494

PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading

SIGNOR-110119

P24723

P04083

1

phosphorylation

up-regulates

0.2

The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.

SIGNOR-202792

P08670

Q13177

0

phosphorylation

down-regulates activity

0.307

In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.

SIGNOR-250243

Q8TF68

P03956

1

transcriptional regulation

up-regulates quantity by expression

0.307

Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence.

SIGNOR-266229

Q02156

P15336

1

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