GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P10636-2	Q05513	0	phosphorylation	down-regulates activity	0.268	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275447
Q9NVI1	Q13535	0	phosphorylation	up-regulates activity	0.623	Alternatively, the locally accumulated ATRIP-ATR might have sufficient activity to phosphorylate FANCI without TOPBP1 stimulation.\|The results described above and our previous studies clearly indicated that FANCI phosphorylation is mediated by ATR kinase in a manner dependent on the FA core complex and FANCD2 protein.	SIGNOR-279320
P51149	Q38SD2	0	phosphorylation	up-regulates activity	0.386	Overall, these data suggest that LRRK1 is able to phosphorylate endogenous Rab7A at Ser72.	SIGNOR-278212
Q14164	P03372	1	phosphorylation	up-regulates	0.341	Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna.	SIGNOR-161834
O43736	P57058	0	phosphorylation	up-regulates activity	0.2	ITM2A is phosphorylated at T35 and the phosphorylation status of ITM2A contributes to breast cancer proliferation. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis.	SIGNOR-273640
Q92985	P03230	0	sumoylation	down-regulates activity	0.2	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.	SIGNOR-266951
P06239	P52757	1	phosphorylation	down-regulates activity	0.2	We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac.	SIGNOR-276240
P09874	P04637	1	relocalization	up-regulates activity	0.559	We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.\|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus.	SIGNOR-261321
Q01167	P06493	0	phosphorylation	up-regulates	0.372	We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.	SIGNOR-167826
P17612	P55064	1	phosphorylation	up-regulates activity	0.2	AQP5 can be directly phosphorylated by PKA at Ser 156 \|Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation.	SIGNOR-272088
P31749	P12931	0	phosphorylation	up-regulates activity	0.677	Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.	SIGNOR-252623
Q9HCE7	P08651	1	ubiquitination	down-regulates quantity	0.329	In addition, Smurf1 knockdown also blocked the degradation of endogenous NFI-C in response to TGF-beta1 (XREF_FIG).\|In particular, Smurf1 and Smurf2 markedly increased the polyubiquitination of NFI-C in the presence of TGF-beta1 (XREF_FIG and XREF_SUPPLEMENTARY).	SIGNOR-278753
P29353	P12931	0	phosphorylation	up-regulates activity	0.666	Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway.	SIGNOR-44870
P27448	Q05513	0	phosphorylation	down-regulates	0.2	Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells	SIGNOR-124221
Q52LW3	P61586	1	gtpase-activating protein	down-regulates activity	0.552	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-260484
P23470	P18206	1	dephosphorylation	down-regulates activity	0.2	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-254731
P30291	P48730	0	phosphorylation	down-regulates quantity by destabilization	0.308	Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ.	SIGNOR-276631
P53778	P15336	1	phosphorylation	up-regulates	0.542	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-65589
P16410	P42681	0	phosphorylation	up-regulates quantity by stabilization	0.498	We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function	SIGNOR-61624
P45983	P61978	1	phosphorylation	up-regulates	0.372	The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein.	SIGNOR-105770
O14920	Q99704	1	phosphorylation	up-regulates	0.253	Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.	SIGNOR-131447
P22681	P43405	1	ubiquitination	down-regulates quantity	0.816	Thus, c-Cbl specifically downregulates Syk levels in the presence of LMP2A.\|c-Cbl promoted LMP2A degradation through ubiquitination, specifically degraded the Syk protein tyrosine kinase in the presence of LMP2A, and inhibited LMP2A induction of the EBV lytic cycle	SIGNOR-278689
Q16665	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	These results indicate that Parkin inhibits HIF-1alpha transcriptional activity.\|Ubiquitination of HIF-1alpha at lysine 477 by Parkin.	SIGNOR-278542
Q14694	Q13315	0	phosphorylation	up-regulates quantity by stabilization	0.252	The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.	SIGNOR-276276
P07101	Q9UQM7	0	phosphorylation	up-regulates	0.256	This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation.	SIGNOR-20912
O15111	P51608	1	phosphorylation	up-regulates activity	0.2	Representative confocal micrographs of 4th day differentiating cultures are shown. (C) IKK\u03b1 promotes MeCP2-dependent BDNF expression.\|The characterization of IKK\u03b1-mediated phosphorylation of MeCP2 at Ser421 and other residues and their effects on the activity of MeCP2 is a topic of current work in our laboratory.	SIGNOR-279459
P49840	O60936	1	phosphorylation	down-regulates quantity by destabilization	0.2	The present study provided evidence that GSK3alpha and beta directly phosphorylates Arc, resulting in its subsequent degradation.	SIGNOR-279179
P35575	Q53ET0	0	transcriptional regulation	up-regulates quantity	0.2	Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256103
P10636	O00141	0	phosphorylation	down-regulates	0.331	Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214	SIGNOR-161288
P24941	Q8IZL9	0	phosphorylation	up-regulates	0.387	P42 is essential for the phosphorylation of thr-160 and activation of cdk2.	SIGNOR-118986
P56945	Q05209	0	dephosphorylation	down-regulates	0.546	Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway.	SIGNOR-109032
Q13485	Q15831	0	phosphorylation	down-regulates activity	0.631	LKB1 inhibits the DNA binding and the transcriptional activity of Smad4.\|We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr 77 of its DNA-binding domain.	SIGNOR-278193
P28482	P41182	1	phosphorylation	down-regulates	0.489	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58481
P17252	Q13043	0	phosphorylation	up-regulates activity	0.2	Mst1 and Mst2 activate PKC\u03b1 to disrupt the LyGDI-Rac complex.\|Thus, the phosphorylation of PKC\u03b1 at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKC\u03b1.	SIGNOR-280146
Q15672	Q16539	0	phosphorylation	up-regulates	0.269	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-173409
P06493	P78549	1	phosphorylation	up-regulates activity	0.33	The main cell cycle kinase Cdk1 directly phosphorylates and activates the trehalase Nth1 to trigger the flux of storage carbohydrates into central carbon metabolism.	SIGNOR-278916
P06493	Q6PGN9	1	phosphorylation	down-regulates activity	0.236	MT-polymerizing activity was decreased from samples with DDA3 phosphorylated by Cdk1 ( xref , lanes 4 vs 6) and Aurora A ( xref , lanes 14 vs 16).\|Taken together, the mitotic Cdk1 and Aurora A kinases inhibit MT polymerization activities and MT bundling activities of DDA3.	SIGNOR-279601
O60343	P31751	0	phosphorylation	down-regulates activity	0.642	AKT2 phosphorylation blocks AS160 function enhancing GLUT4 intracellular vesicular transport, and as such promotes glucose uptake following insulin release .\|Notable mechanisms promoting this involves AKT2 mediated phosphorylation of the Rab-GTPase-activating protein TBC1D4, also known as AS160.	SIGNOR-280179
P27361	P49585	1	phosphorylation	down-regulates	0.46	Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.	SIGNOR-134841
P01008	P00748	1	cleavage	down-regulates activity	0.6	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264139
P17612	O95295	1	phosphorylation	up-regulates activity	0.307	PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation	SIGNOR-250053
P48454	P21333	1	dephosphorylation	down-regulates quantity by destabilization	0.2	Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin \|Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.	SIGNOR-248507
Q9Y4G8	Q04759	0	phosphorylation	up-regulates	0.2	After t-cell activation, the direct phosphorylation of rapgef2 at ser960 by pkc- theta regulates rap1 activation as well as lfa-1 adhesiveness to icam-1. Pkc- theta and its effector rapgef2 are critical factors in tcr signaling to rap1	SIGNOR-181186
P59595	P01100	1	transcriptional regulation	up-regulates quantity by expression	0.2	The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well	SIGNOR-260726
Q70SY1	Q14703	0	cleavage	up-regulates	0.561	Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei	SIGNOR-151309
Q92949	O14645	1	transcriptional regulation	up-regulates quantity by expression	0.394	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266933
P08709	P04070	0	cleavage	down-regulates activity	0.237	Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes	SIGNOR-263527
P24158	P25116	1	cleavage	down-regulates activity	0.42	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263577
P63165	P29590	1	sumoylation	up-regulates	0.78	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins\|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites\| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.	SIGNOR-261786
P07949	P31749	1	phosphorylation	up-regulates	0.323	The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity	SIGNOR-252619
P12931	Q92529-2	1	phosphorylation	up-regulates activity	0.576	We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.	SIGNOR-273921
P53805	Q99759	0	phosphorylation	up-regulates	0.448	Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation	SIGNOR-102294
Q96ST2	Q9Y243	0	phosphorylation	up-regulates activity	0.381	The data presented in this report confirmed the differential phosphorylation of IWS1 at Ser720/Thr721 by Akt3 and Akt1 and showed that its phosphorylation at this site is required for the recruitment of SetD2 to the Spt6-IWS1-Aly/REF complex.	SIGNOR-273496
P41743	P29474	1	phosphorylation	down-regulates activity	0.2	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251635
Q96PU5	Q9BSA4	1	polyubiquitination	down-regulates quantity by destabilization	0.286	Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein.	SIGNOR-272632
P19474	Q92985	1	ubiquitination	down-regulates quantity by destabilization	0.677	Furthermore, this Ro52 mediated degradation of IRF7 was inhibited in the presence of MG132, a proteasome inhibitor, indicating that IRF7 is targeted to the proteasome for degradation (XREF_FIG).\|Ro52 ubiquitinates IRF7 in a dose dependent manner.	SIGNOR-278619
P00519	P29474	1	phosphorylation	up-regulates activity	0.2	Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.	SIGNOR-277519
P29120	P10997	1	cleavage	up-regulates activity	0.446	The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule	SIGNOR-261782
P49841	P17252	0	phosphorylation	down-regulates	0.357	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188581
P36776	P31749	0	phosphorylation	up-regulates activity	0.253	In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity.	SIGNOR-265724
Q14432	P17252	0	phosphorylation	up-regulates	0.2	Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.	SIGNOR-184452
P49840	Q92908	1	phosphorylation	down-regulates quantity by destabilization	0.265	Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin	SIGNOR-253156
Q12968	P05231	1	transcriptional regulation	up-regulates quantity by expression	0.283	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. \|Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251732
Q15139	P53367	1	phosphorylation	up-regulates	0.385	We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway.	SIGNOR-202101
Q00526	P18846	1	phosphorylation	up-regulates	0.2	Cyclin-dependent kinase 3-mediated activating transcription factor 1 phosphorylation enhances cell transformationwe found that cdk3 phosphorylates activating transcription factor 1 (atf1) at serine 63 and enhances the transactivation and transcriptional activities of atf1.	SIGNOR-180920
P31749	O15111	1	phosphorylation	up-regulates	0.668	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187006
P11441	Q92995	0	deubiquitination	up-regulates activity	0.61	USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.	SIGNOR-272857
Q9Y237	P35568	1	isomerization	up-regulates activity	0.2	In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells\|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation\|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events	SIGNOR-265756
P0DP23	P68400	0	phosphorylation	down-regulates activity	0.422	Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third.	SIGNOR-266355
P43629	P17252	0	phosphorylation	down-regulates activity	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.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII.	SIGNOR-276080
O75417	Q00987	0	polyubiquitination	down-regulates quantity by destabilization	0.2	DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation	SIGNOR-272729
Q15306	P12931	0	phosphorylation	up-regulates activity	0.273	Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation.\|We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target B cell integration cluster in Epstein-Barr virus-transformed cells.	SIGNOR-279287
P42771	P40424	0	transcriptional regulation	up-regulates quantity by expression	0.308	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267239
P52738	O75015	1	transcriptional regulation	down-regulates quantity by repression	0.2	Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.	SIGNOR-266214
P42229	O14543	1	transcriptional regulation	up-regulates quantity by expression	0.637	We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling	SIGNOR-261548
P29350	O94916	1	dephosphorylation	down-regulates activity	0.343	We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity	SIGNOR-248467
P31749	Q96CG3	1	phosphorylation	up-regulates activity	0.2	For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs.	SIGNOR-273542
O94925	Q02156	0	phosphorylation	up-regulates activity	0.2	PKCε is the kinase that phosphorylates GAC at Ser314.	SIGNOR-277387
Q9Y4P1	Q9P289	0	phosphorylation	up-regulates activity	0.2	ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux.	SIGNOR-275833
Q16539	P49137	1	phosphorylation	up-regulates activity	0.769	Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation	SIGNOR-44351
P51674	P17252	0	phosphorylation	up-regulates activity	0.324	In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells.	SIGNOR-263163
Q15119	P31749	1	phosphorylation	up-regulates activity	0.749	PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a gain control for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity	SIGNOR-249630
P12830	P48729	0	phosphorylation	down-regulates activity	0.312	Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts\|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846	SIGNOR-274045
Q13153	O15143	1	phosphorylation	up-regulates	0.531	The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21	SIGNOR-121642
P67870	P55957	1	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
Q15119	P08559	1	phosphorylation	down-regulates	0.679	Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.	SIGNOR-33141
Q9Y6Q9	P48730	0	phosphorylation	up-regulates	0.284	In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1.	SIGNOR-184946
Q12778	Q13043	0	phosphorylation	up-regulates	0.595	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.	SIGNOR-191847
P49841	P28482	0	phosphorylation	down-regulates activity	0.383	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262524
P78357	Q05655	0	phosphorylation	down-regulates activity	0.2	Inhibition of PKCdelta increased p190 activity, while PKCdelta overexpression diminished p190 activity.\|We further show that PKC\u03b4 was able to phosphorylate and bind distinct domains of p190.	SIGNOR-279260
Q15831	P27361	0	phosphorylation	down-regulates activity	0.39	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-209880
Q16236	P00390	1	transcriptional regulation	up-regulates quantity by expression	0.405	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy	SIGNOR-279871
P15311	P31751	0	phosphorylation	up-regulates	0.375	Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression	SIGNOR-130260
O60885	P24928	1	phosphorylation	up-regulates	0.448	We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality	SIGNOR-197012
Q9NZQ7	Q9UNE7	0	destabilization	down-regulates quantity by destabilization	0.2	Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly	SIGNOR-274979
O14757	P27816	1	phosphorylation	down-regulates quantity by destabilization	0.2	MAP4 is a novel target of FBXW7 via the phosphorylated threonine T521 modified by CHEK1 in ESCC. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system.	SIGNOR-277846
Q9Y243	P99999	1	phosphorylation	down-regulates activity	0.265	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277235
P31751	P15056	1	phosphorylation	down-regulates	0.272	We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf	SIGNOR-78689
P61224	Q8WZA2	0	guanine nucleotide exchange factor	up-regulates activity	0.811	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263955
P19784	Q712K3	1	phosphorylation	up-regulates activity	0.449	UBC3B is specifically phosphorylated by CK2 in vitro and in vivo. We mapped by deletions and site directed mutagenesis the phosphorylation site to a serine residue within the C-terminal domain in position 233 of UBC3B and in the corresponding serine residue of UBC3. \| Following CK2-dependent phosphorylation both UBC3B and UBC3 bind to the F-box protein beta-TrCP, the substrate recognition subunit of an SCF (Skp1, Cul1, F-box) ubiquitin ligase. Furthermore, we observed that co-transfection of CK2alpha' together with UBC3B, but not with UBC3DeltaC, enhances the degradation of beta-catenin.	SIGNOR-251047

P10636-2

Q05513

0

phosphorylation

down-regulates activity

0.268

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275447

Q9NVI1

Q13535

0

phosphorylation

up-regulates activity

0.623

Alternatively, the locally accumulated ATRIP-ATR might have sufficient activity to phosphorylate FANCI without TOPBP1 stimulation.|The results described above and our previous studies clearly indicated that FANCI phosphorylation is mediated by ATR kinase in a manner dependent on the FA core complex and FANCD2 protein.

SIGNOR-279320

P51149

Q38SD2

0

phosphorylation

up-regulates activity

0.386

Overall, these data suggest that LRRK1 is able to phosphorylate endogenous Rab7A at Ser72.

SIGNOR-278212

Q14164

P03372

1

phosphorylation

up-regulates

0.341

Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna.

SIGNOR-161834

O43736

P57058

0

phosphorylation

up-regulates activity

0.2

ITM2A is phosphorylated at T35 and the phosphorylation status of ITM2A contributes to breast cancer proliferation. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis.

SIGNOR-273640

Q92985

P03230

0

sumoylation

down-regulates activity

0.2

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.

SIGNOR-266951

P06239

P52757

1

phosphorylation

down-regulates activity

0.2

We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac.

SIGNOR-276240

P09874

P04637

1

relocalization

up-regulates activity

0.559

We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus.

SIGNOR-261321

Q01167

P06493

0

phosphorylation

up-regulates

0.372

We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.

SIGNOR-167826

P17612

P55064

1

phosphorylation

up-regulates activity

0.2

AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation.

SIGNOR-272088

P31749

P12931

0

phosphorylation

up-regulates activity

0.677

Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.

SIGNOR-252623

Q9HCE7

P08651

1

ubiquitination

down-regulates quantity

0.329

In addition, Smurf1 knockdown also blocked the degradation of endogenous NFI-C in response to TGF-beta1 (XREF_FIG).|In particular, Smurf1 and Smurf2 markedly increased the polyubiquitination of NFI-C in the presence of TGF-beta1 (XREF_FIG and XREF_SUPPLEMENTARY).

SIGNOR-278753

P29353

P12931

0

phosphorylation

up-regulates activity

0.666

Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway.

SIGNOR-44870

P27448

Q05513

0

phosphorylation

down-regulates

0.2

Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells

SIGNOR-124221

Q52LW3

P61586

1

gtpase-activating protein

down-regulates activity

0.552

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-260484

P23470

P18206

1

dephosphorylation

down-regulates activity

0.2

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-254731

P30291

P48730

0

phosphorylation

down-regulates quantity by destabilization

0.308

Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ.

SIGNOR-276631

P53778

P15336

1

phosphorylation

up-regulates

0.542

Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target

SIGNOR-65589

P16410

P42681

0

phosphorylation

up-regulates quantity by stabilization

0.498

We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function

SIGNOR-61624

P45983

P61978

1

phosphorylation

up-regulates

0.372

The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein.

SIGNOR-105770

O14920

Q99704

1

phosphorylation

up-regulates

0.253

Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.

SIGNOR-131447

P22681

P43405

1

ubiquitination

down-regulates quantity

0.816

Thus, c-Cbl specifically downregulates Syk levels in the presence of LMP2A.|c-Cbl promoted LMP2A degradation through ubiquitination, specifically degraded the Syk protein tyrosine kinase in the presence of LMP2A, and inhibited LMP2A induction of the EBV lytic cycle

SIGNOR-278689

Q16665

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

These results indicate that Parkin inhibits HIF-1alpha transcriptional activity.|Ubiquitination of HIF-1alpha at lysine 477 by Parkin.

SIGNOR-278542

Q14694

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.252

The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.

SIGNOR-276276

P07101

Q9UQM7

0

phosphorylation

up-regulates

0.256

This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation.

SIGNOR-20912

O15111

P51608

1

phosphorylation

up-regulates activity

0.2

Representative confocal micrographs of 4th day differentiating cultures are shown. (C) IKK\u03b1 promotes MeCP2-dependent BDNF expression.|The characterization of IKK\u03b1-mediated phosphorylation of MeCP2 at Ser421 and other residues and their effects on the activity of MeCP2 is a topic of current work in our laboratory.

SIGNOR-279459

P49840

O60936

1

phosphorylation

down-regulates quantity by destabilization

0.2

The present study provided evidence that GSK3alpha and beta directly phosphorylates Arc, resulting in its subsequent degradation.

SIGNOR-279179

P35575

Q53ET0

0

transcriptional regulation

up-regulates quantity

0.2

Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB

SIGNOR-256103

P10636

O00141

0

phosphorylation

down-regulates

0.331

Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214

SIGNOR-161288

P24941

Q8IZL9

0

phosphorylation

up-regulates

0.387

P42 is essential for the phosphorylation of thr-160 and activation of cdk2.

SIGNOR-118986

P56945

Q05209

0

dephosphorylation

down-regulates

0.546

Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway.

SIGNOR-109032

Q13485

Q15831

0

phosphorylation

down-regulates activity

0.631

LKB1 inhibits the DNA binding and the transcriptional activity of Smad4.|We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr 77 of its DNA-binding domain.

SIGNOR-278193

P28482

P41182

1

phosphorylation

down-regulates

0.489

Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.

SIGNOR-58481

P17252

Q13043

0

phosphorylation

up-regulates activity

0.2

Mst1 and Mst2 activate PKC\u03b1 to disrupt the LyGDI-Rac complex.|Thus, the phosphorylation of PKC\u03b1 at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKC\u03b1.

SIGNOR-280146

Q15672

Q16539

0

phosphorylation

up-regulates

0.269

Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro

SIGNOR-173409

P06493

P78549

1

phosphorylation

up-regulates activity

0.33

The main cell cycle kinase Cdk1 directly phosphorylates and activates the trehalase Nth1 to trigger the flux of storage carbohydrates into central carbon metabolism.

SIGNOR-278916

P06493

Q6PGN9

1

phosphorylation

down-regulates activity

0.236

MT-polymerizing activity was decreased from samples with DDA3 phosphorylated by Cdk1 ( xref , lanes 4 vs 6) and Aurora A ( xref , lanes 14 vs 16).|Taken together, the mitotic Cdk1 and Aurora A kinases inhibit MT polymerization activities and MT bundling activities of DDA3.

SIGNOR-279601

O60343

P31751

0

phosphorylation

down-regulates activity

0.642

AKT2 phosphorylation blocks AS160 function enhancing GLUT4 intracellular vesicular transport, and as such promotes glucose uptake following insulin release .|Notable mechanisms promoting this involves AKT2 mediated phosphorylation of the Rab-GTPase-activating protein TBC1D4, also known as AS160.

SIGNOR-280179

P27361

P49585

1

phosphorylation

down-regulates

0.46

Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.

SIGNOR-134841

P01008

P00748

1

cleavage

down-regulates activity

0.6

Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1

SIGNOR-264139

P17612

O95295

1

phosphorylation

up-regulates activity

0.307

PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation

SIGNOR-250053

P48454

P21333

1

dephosphorylation

down-regulates quantity by destabilization

0.2

Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.

SIGNOR-248507

Q9Y4G8

Q04759

0

phosphorylation

up-regulates

0.2

After t-cell activation, the direct phosphorylation of rapgef2 at ser960 by pkc- theta regulates rap1 activation as well as lfa-1 adhesiveness to icam-1. Pkc- theta and its effector rapgef2 are critical factors in tcr signaling to rap1

SIGNOR-181186

P59595

P01100

1

transcriptional regulation

up-regulates quantity by expression

0.2

The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well

SIGNOR-260726

Q70SY1

Q14703

0

cleavage

up-regulates

0.561

Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei

SIGNOR-151309

Q92949

O14645

1

transcriptional regulation

up-regulates quantity by expression

0.394

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266933

P08709

P04070

0

cleavage

down-regulates activity

0.237

Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes

SIGNOR-263527

P24158

P25116

1

cleavage

down-regulates activity

0.42

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.

SIGNOR-263577

P63165

P29590

1

sumoylation

up-regulates

0.78

We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.

SIGNOR-261786

P07949

P31749

1

phosphorylation

up-regulates

0.323

The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity

SIGNOR-252619

P12931

Q92529-2

1

phosphorylation

up-regulates activity

0.576

We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.

SIGNOR-273921

P53805

Q99759

0

phosphorylation

up-regulates

0.448

Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation

SIGNOR-102294

Q96ST2

Q9Y243

0

phosphorylation

up-regulates activity

0.381

The data presented in this report confirmed the differential phosphorylation of IWS1 at Ser720/Thr721 by Akt3 and Akt1 and showed that its phosphorylation at this site is required for the recruitment of SetD2 to the Spt6-IWS1-Aly/REF complex.

SIGNOR-273496

P41743

P29474

1

phosphorylation

down-regulates activity

0.2

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251635

Q96PU5

Q9BSA4

1

polyubiquitination

down-regulates quantity by destabilization

0.286

Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein.

SIGNOR-272632

P19474

Q92985

1

ubiquitination

down-regulates quantity by destabilization

0.677

Furthermore, this Ro52 mediated degradation of IRF7 was inhibited in the presence of MG132, a proteasome inhibitor, indicating that IRF7 is targeted to the proteasome for degradation (XREF_FIG).|Ro52 ubiquitinates IRF7 in a dose dependent manner.

SIGNOR-278619

P00519

P29474

1

phosphorylation

up-regulates activity

0.2

Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.

SIGNOR-277519

P29120

P10997

1

cleavage

up-regulates activity

0.446

The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule

SIGNOR-261782

P49841

P17252

0

phosphorylation

down-regulates

0.357

Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).

SIGNOR-188581

P36776

P31749

0

phosphorylation

up-regulates activity

0.253

In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity.

SIGNOR-265724

Q14432

P17252

0

phosphorylation

up-regulates

0.2

Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.

SIGNOR-184452

P49840

Q92908

1

phosphorylation

down-regulates quantity by destabilization

0.265

Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin

SIGNOR-253156

Q12968

P05231

1

transcriptional regulation

up-regulates quantity by expression

0.283

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.

SIGNOR-251732

Q15139

P53367

1

phosphorylation

up-regulates

0.385

We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway.

SIGNOR-202101

Q00526

P18846

1

phosphorylation

up-regulates

0.2

Cyclin-dependent kinase 3-mediated activating transcription factor 1 phosphorylation enhances cell transformationwe found that cdk3 phosphorylates activating transcription factor 1 (atf1) at serine 63 and enhances the transactivation and transcriptional activities of atf1.

SIGNOR-180920

P31749

O15111

1

phosphorylation

up-regulates

0.668

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

SIGNOR-187006

P11441

Q92995

0

deubiquitination

up-regulates activity

0.61

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

SIGNOR-272857

Q9Y237

P35568

1

isomerization

up-regulates activity

0.2

In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events

SIGNOR-265756

P0DP23

P68400

0

phosphorylation

down-regulates activity

0.422

Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third.

SIGNOR-266355

P43629

P17252

0

phosphorylation

down-regulates activity

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.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII.

SIGNOR-276080

O75417

Q00987

0

polyubiquitination

down-regulates quantity by destabilization

0.2

DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation

SIGNOR-272729

Q15306

P12931

0

phosphorylation

up-regulates activity

0.273

Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation.|We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target B cell integration cluster in Epstein-Barr virus-transformed cells.

SIGNOR-279287

P42771

P40424

0

transcriptional regulation

up-regulates quantity by expression

0.308

We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.

SIGNOR-267239

P52738

O75015

1

transcriptional regulation

down-regulates quantity by repression

0.2

Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.

SIGNOR-266214

P42229

O14543

1

transcriptional regulation

up-regulates quantity by expression

0.637

We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling

SIGNOR-261548

P29350

O94916

1

dephosphorylation

down-regulates activity

0.343

We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity

SIGNOR-248467

P31749

Q96CG3

1

phosphorylation

up-regulates activity

0.2

For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs.

SIGNOR-273542

O94925

Q02156

0

phosphorylation

up-regulates activity

0.2

PKCε is the kinase that phosphorylates GAC at Ser314.

SIGNOR-277387

Q9Y4P1

Q9P289

0

phosphorylation

up-regulates activity

0.2

ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux.

SIGNOR-275833

Q16539

P49137

1

phosphorylation

up-regulates activity

0.769

Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation

SIGNOR-44351

P51674

P17252

0

phosphorylation

up-regulates activity

0.324

In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells.

SIGNOR-263163

Q15119

P31749

1

phosphorylation

up-regulates activity

0.749

PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a gain control for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity

SIGNOR-249630

P12830

P48729

0

phosphorylation

down-regulates activity

0.312

Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846

SIGNOR-274045

Q13153

O15143

1

phosphorylation

up-regulates

0.531

The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21

SIGNOR-121642

P67870

P55957

1

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

Q15119

P08559

1

phosphorylation

down-regulates

0.679

Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.

SIGNOR-33141

Q9Y6Q9

P48730

0

phosphorylation

up-regulates

0.284

In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1.

SIGNOR-184946

Q12778

Q13043

0

phosphorylation

up-regulates

0.595

Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.

SIGNOR-191847

P49841

P28482

0

phosphorylation

down-regulates activity

0.383

We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels

SIGNOR-262524

P78357

Q05655

0

phosphorylation

down-regulates activity

0.2

Inhibition of PKCdelta increased p190 activity, while PKCdelta overexpression diminished p190 activity.|We further show that PKC\u03b4 was able to phosphorylate and bind distinct domains of p190.

SIGNOR-279260

Q15831

P27361

0

phosphorylation

down-regulates activity

0.39

Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.

SIGNOR-209880

Q16236

P00390

1

transcriptional regulation

up-regulates quantity by expression

0.405

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy

SIGNOR-279871

P15311

P31751

0

phosphorylation

up-regulates

0.375

Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression

SIGNOR-130260

O60885

P24928

1

phosphorylation

up-regulates

0.448

We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality

SIGNOR-197012

Q9NZQ7

Q9UNE7

0

destabilization

down-regulates quantity by destabilization

0.2

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

SIGNOR-274979

O14757

P27816

1

phosphorylation

down-regulates quantity by destabilization

0.2

MAP4 is a novel target of FBXW7 via the phosphorylated threonine T521 modified by CHEK1 in ESCC. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system.

SIGNOR-277846

Q9Y243

P99999

1

phosphorylation

down-regulates activity

0.265

Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.

SIGNOR-277235

P31751

P15056

1

phosphorylation

down-regulates

0.272

We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf

SIGNOR-78689

P61224

Q8WZA2

0

guanine nucleotide exchange factor

up-regulates activity

0.811

Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.

SIGNOR-263955

P19784

Q712K3

1

phosphorylation

up-regulates activity

0.449

UBC3B is specifically phosphorylated by CK2 in vitro and in vivo. We mapped by deletions and site directed mutagenesis the phosphorylation site to a serine residue within the C-terminal domain in position 233 of UBC3B and in the corresponding serine residue of UBC3. | Following CK2-dependent phosphorylation both UBC3B and UBC3 bind to the F-box protein beta-TrCP, the substrate recognition subunit of an SCF (Skp1, Cul1, F-box) ubiquitin ligase. Furthermore, we observed that co-transfection of CK2alpha' together with UBC3B, but not with UBC3DeltaC, enhances the degradation of beta-catenin.

SIGNOR-251047