GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P12931	Q9Y6K9	1	phosphorylation	down-regulates activity	0.416	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.	SIGNOR-276370
P0DP25	P00533	0	phosphorylation	down-regulates	0.382	Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-266335
Q8TBB1	P11274	1	ubiquitination	down-regulates quantity by destabilization	0.267	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272903
Q96EP1	Q12824	1	polyubiquitination	down-regulates quantity by destabilization	0.316	Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.	SIGNOR-271458
P15336	P31751	0	phosphorylation	up-regulates activity	0.426	Taken together, these data suggest that AMPK regulates EC migration through phosphorylation of AKT2, which promotes ATF2 transactivation of MMP-2 during EC migration.\|Within this subgroup, we chose AKT2 for analysis because AKT2 phosphorylates activating transcription factor 2 (ATF2) [ xref , xref ].	SIGNOR-280178
P62140	P29474	1	dephosphorylation	up-regulates activity	0.2	The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation	SIGNOR-248574
Q13469	Q86Y07	0	phosphorylation	up-regulates	0.369	We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain.	SIGNOR-199263
Q9HCK8	P11137	1	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268916
P25815	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.292	S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.	SIGNOR-272919
Q9Y4G8	P46934	0	ubiquitination	down-regulates quantity	0.401	In line with the previous result (XREF_FIG), overexpression of NEDD4-1 reduced the level of CNrasGEF significantly (XREF_FIG).\|NEDD4-1 ubiquitinates CNrasGEF in glioma cells.	SIGNOR-278705
P25098	Q16539	1	phosphorylation	down-regulates	0.2	Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates	SIGNOR-150152
P11802	P23760	1	phosphorylation	up-regulates activity	0.296	In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.\|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro .	SIGNOR-278512
P04637	P21675	0	phosphorylation	down-regulates	0.681	Phosphorylation on thr-55 by taf1 mediates degradation of p53	SIGNOR-123651
P60983	P17612	0	phosphorylation	up-regulates activity	0.307	Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82.	SIGNOR-249983
O94826	Q13627	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of TOM70 Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase.	SIGNOR-279994
Q14493	Q6FI13	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265396
Q9P212	P01112	1	guanine nucleotide exchange factor	up-regulates	0.578	The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp.	SIGNOR-82859
Q93084	P14921	0	transcriptional regulation	up-regulates quantity by expression	0.326	Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold.	SIGNOR-261601
P35240	Q9UKE5	0	phosphorylation	up-regulates activity	0.2	Consistently with TNIK modulating Merlin, we also observed reduced YAP levels following TNIK knockdown in LK2 and NCI-H520 cells (Supplementary Fig. S7B).\|Using in vitro kinase assays followed by phosphopeptide mapping, and mass spectrometry analysis on Merlin isolated from cells co-expressing TNIK and Merlin, we determined that TNIK could phosphorylate Merlin at S13, T272, S315, and T576 (Fig. 4B, Supplementary Fig. S4D, and Supplementary Table S3).	SIGNOR-278386
O43307	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.834	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-260534
P68400	P30519	1	phosphorylation	up-regulates activity	0.335	Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. \| CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2	SIGNOR-250895
P54132	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.259	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.	SIGNOR-276906
Q9Y618	P10275	1	acetylation	down-regulates	0.562	In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.	SIGNOR-101286
O43490	Q15262	0	dephosphorylation	down-regulates activity	0.2	PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.\|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo.	SIGNOR-277133
O96017	Q14457	1	phosphorylation	up-regulates activity	0.299	We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.\|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration	SIGNOR-264557
P32929	Q13237	0	phosphorylation	down-regulates activity	0.244	CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) of CSE, inhibiting the production of H2S.	SIGNOR-275800
P41240	Q96J02	1	phosphorylation	down-regulates activity	0.2	CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro.	SIGNOR-245327
Q13469	P16298	0	dephosphorylation	up-regulates	0.614	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-233438
P78368	P07948	1	phosphorylation	up-regulates quantity by stabilization	0.2	Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.	SIGNOR-275397
Q9HAW4	Q9UKB1	0	ubiquitination	down-regulates	0.345	Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase.	SIGNOR-148438
Q16539	P04150	1	phosphorylation	up-regulates	0.511	We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.	SIGNOR-135198
Q6R6M4	Q99538	1	deubiquitination	down-regulates quantity by destabilization	0.309	We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation.	SIGNOR-272854
Q7Z6J0	P31751	0	phosphorylation	down-regulates	0.389	Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac	SIGNOR-155233
Q86WV6	Q99942	0	ubiquitination	down-regulates quantity by destabilization	0.2	The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection.	SIGNOR-271484
O60381	Q16539	0	phosphorylation	up-regulates	0.43	A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.	SIGNOR-119138
Q9H4G4	P51617	0	phosphorylation	up-regulates activity	0.325	We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion.	SIGNOR-262887
Q00535	P07814	1	phosphorylation	down-regulates	0.2	Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation	SIGNOR-187383
Q13043	P10275	1	phosphorylation	down-regulates activity	0.2	Here we showed that MST1 is an androgen receptor kinase and phosphorylates androgen receptor at Ser-650 ( ).\|Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter.	SIGNOR-280143
Q9BRK5	Q8IXL6	0	phosphorylation	up-regulates activity	0.2	Together, these results indicate that Fam20C kinase activity drives the sorting and secretion of the Cab45 dependent client LyzC.\|We show that Fam20C phosphorylates Cab45 on distinct residues and thereby decreases Cab45 retention in the TGN.	SIGNOR-279330
Q99942	O43511	1	ubiquitination	down-regulates quantity by destabilization	0.2	E3 ubiquitin ligase Rma1 is involved in Pendrin degradation	SIGNOR-271497
P53350	O43663	1	phosphorylation	down-regulates activity	0.723	Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.\|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase.	SIGNOR-279645
O43497	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.261	Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression.	SIGNOR-264034
P35813	P46937	1	dephosphorylation	up-regulates activity	0.269	Although the authors show an in vitro kinase assay where PPM1A supposedly dephosphorylates YAP on Ser127, Fig. 4A lacks a positive control to ensure that PPM1A purified from cells is active.\|The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.	SIGNOR-276984
P54764	P51692	1	phosphorylation	up-regulates activity	0.375	We have shown here that EphA4 can phosphorylate STAT5B, but it is not yet clear whether the nuclear translocation of phosphorylated STAT5B is enhanced by EphA4.	SIGNOR-278934
Q504Q3	Q13315	0	phosphorylation	up-regulates activity	0.2	Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52.	SIGNOR-273508
P05771-2	P62714	0	dephosphorylation	down-regulates activity	0.469	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248587
Q9C0B5	Q15910	1	palmitoylation	down-regulates activity	0.2	Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2.	SIGNOR-261144
P23588	P31749	0	phosphorylation	up-regulates	0.393	Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b.	SIGNOR-252520
Q14938	P54764	1	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268908
P40763	P22455	0	phosphorylation	up-regulates activity	0.402	Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.	SIGNOR-251142
P61586	Q8IW93	0	guanine nucleotide exchange factor	up-regulates activity	0.636	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-260543
P40763	P22607	0	phosphorylation	up-regulates activity	0.631	Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.	SIGNOR-251139
Q15796	P27037	0	phosphorylation	up-regulates activity	0.71	In ACVR2A/B dKO parental cells, only ACVR2A , but not ACVR2A , could rescue both pSMAD2 and pSMAD1/5 (Fig\u00a04B).\|In marked contrast, in ACVR2A/B dKO HOM1 cells, ACVR2A restored SMAD1/5 phosphorylation, but not SMAD2 phosphorylation (Fig\u00a04C).	SIGNOR-279786
P11387	P78527	0	phosphorylation	down-regulates quantity by destabilization	0.448	Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.	SIGNOR-277352
P15172	P08047	1	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
P49841	Q13541	1	phosphorylation	down-regulates activity	0.364	We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation.	SIGNOR-236026
Q92879	P31749	0	phosphorylation	up-regulates activity	0.41	In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA.	SIGNOR-280173
Q96AX9	Q9Y219	1	ubiquitination	up-regulates	0.809	Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.	SIGNOR-137922
P49757	Q6PML9	0	ubiquitination	down-regulates quantity by destabilization	0.2	Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation.	SIGNOR-113704
P31749	P67809	1	phosphorylation	up-regulates	0.558	Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102	SIGNOR-252521
P17252	P06127	1	phosphorylation	up-regulates	0.339	Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.	SIGNOR-85179
P41743	Q92934	1	phosphorylation	down-regulates	0.32	In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer	SIGNOR-172894
Q13393	P17252	0	phosphorylation	up-regulates	0.714	Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.	SIGNOR-69938
Q96RU2	Q9HA47	1	deubiquitination	up-regulates quantity by stabilization	0.2	We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.	SIGNOR-275855
O60674	Q92858	1	phosphorylation	up-regulates quantity	0.339	We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling.	SIGNOR-262201
P43146	O00555	1	null	up-regulates activity	0.2	DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.	SIGNOR-268293
P05067	P06241	0	phosphorylation	up-regulates quantity	0.451	Fyn induced phosphorylation of APP at Tyr-757 of the (757)YENPTY(762) motif and increased cell surface expression of APP.	SIGNOR-278378
Q15759	P15923	1	phosphorylation	up-regulates	0.436	Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription, while the nonphosphorylatable e47 mutant ser140ala fails to heterodimerize with myod and displays impaired myogenic potentia	SIGNOR-134190
P06493	P35251	1	phosphorylation	down-regulates activity	0.245	Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA\|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. \|Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA.	SIGNOR-265504
O14939	P00533	0	phosphorylation	up-regulates activity	0.516	Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold	SIGNOR-251095
P29590	P06493	0	phosphorylation	down-regulates	0.345	Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation.	SIGNOR-176033
Q08881	Q8TDQ0	1	phosphorylation	up-regulates activity	0.31	When we tested the effect of ITK on the Y265 mutant, we found a pronounced reduction of ITK-mediated tyrosine phosphorylation, suggesting that Y265 is specifically phosphorylated by ITK (Fig. 3B). Our results demonstrate that specific phosphorylation of Y265 of Tim-3 occurs in the presence of galectin-9, probably through a receptor-ligand interaction. Phosphorylation of Y265, which is situated in a highly conserved SH2 binding domain, could result in the recruitment of SH2 containing adaptor proteins and trigger downstream signalling events regulating the fate of Tim-3 expressing T-cells.	SIGNOR-273644
P37275	Q13315	0	phosphorylation	up-regulates activity	0.474	Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation.\|Therefore, ATM dependent phosphorylation of ZEB1 at S585 is crucial for IR induced stabilization of ZEB1 but not the interaction between ZEB1 and USP7.	SIGNOR-278329
Q01130	Q00987	1	transcriptional regulation	up-regulates quantity by expression	0.279	Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2.	SIGNOR-260076
Q00535	P27695	1	phosphorylation	up-regulates activity	0.377	Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5.	SIGNOR-276337
Q9BZI1	P27361	0	phosphorylation	up-regulates activity	0.2	To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target.	SIGNOR-263061
Q99683	Q5S007	0	phosphorylation	up-regulates activity	0.325	LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site.	SIGNOR-277251
O96013	O94806	0	phosphorylation	up-regulates activity	0.252	PAK4 activity is regulated by an autoinhibitory domain that is released upon RhoGTPase binding as well as phosphorylation at Ser474 in the activation loop of the kinase domain. In the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1)	SIGNOR-275931
P18031	P35222	1	dephosphorylation	up-regulates activity	0.66	PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.\|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.\|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.	SIGNOR-277121
P14373	O00750	1	ubiquitination	down-regulates	0.402	We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity.	SIGNOR-177935
O60674	Q6N021	1	phosphorylation	up-regulates activity	0.418	Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.	SIGNOR-277289
Q8IYT8	P09467	1	phosphorylation	down-regulates activity	0.2	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274039
P01106	P56178	0	transcriptional regulation	up-regulates quantity	0.274	Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells	SIGNOR-241914
Q9H1R3	Q06413	1	phosphorylation	up-regulates activity	0.402	Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.	SIGNOR-238118
P27361	Q13153	1	phosphorylation	down-regulates	0.337	Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.	SIGNOR-123074
P41279	Q02750	1	phosphorylation	up-regulates	0.574	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf	SIGNOR-36453
O43324	Q05086	0	ubiquitination	down-regulates quantity	0.2	These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.\|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling.	SIGNOR-278680
P68400	O43889	1	phosphorylation	down-regulates quantity by destabilization	0.2	Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3.	SIGNOR-277501
P68400	O60341	1	phosphorylation	up-regulates activity	0.318	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276903
P49841	P12931	1	phosphorylation	up-regulates activity	0.383	P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity.	SIGNOR-278444
Q9UER7	Q13315	0	phosphorylation	down-regulates	0.499	The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation.	SIGNOR-200889
Q9UPX8	O95886	0	relocalization	up-regulates activity	0.788	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264593
Q13191	O00459	1	ubiquitination	down-regulates activity	0.499	Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. it can be postulated that Cbl-b, as an E3 Ub ligase, may play a general role in functional regulation of its target proteins through ubiquitination in a protein degradation-independent manner.	SIGNOR-271424
Q2M1Z3	P63000	1	gtpase-activating protein	down-regulates activity	0.566	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-260489
Q68EM7	P17612	0	phosphorylation	down-regulates activity	0.2	Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. \|ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex.	SIGNOR-272155
Q92733	Q9UI95	1	relocalization	up-regulates	0.496	We found that the human papillary renal cell carcinoma-associated proteinprccinteracts with the cell cycle control proteinmad2b, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function.	SIGNOR-126516
Q53ET0	Q9H0K1	0	phosphorylation	down-regulates	0.743	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-142218
P27986	Q15139	0	phosphorylation	up-regulates activity	0.2	PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration.	SIGNOR-276426
P35813	Q15796	1	dephosphorylation	down-regulates	0.668	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-146919
Q96CW1	P00533	1	relocalization	down-regulates	0.524	The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr.	SIGNOR-185124

P12931

Q9Y6K9

1

phosphorylation

down-regulates activity

0.416

Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.

SIGNOR-276370

P0DP25

P00533

0

phosphorylation

down-regulates

0.382

Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.

SIGNOR-266335

Q8TBB1

P11274

1

ubiquitination

down-regulates quantity by destabilization

0.267

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

SIGNOR-272903

Q96EP1

Q12824

1

polyubiquitination

down-regulates quantity by destabilization

0.316

Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.

SIGNOR-271458

P15336

P31751

0

phosphorylation

up-regulates activity

0.426

Taken together, these data suggest that AMPK regulates EC migration through phosphorylation of AKT2, which promotes ATF2 transactivation of MMP-2 during EC migration.|Within this subgroup, we chose AKT2 for analysis because AKT2 phosphorylates activating transcription factor 2 (ATF2) [ xref , xref ].

SIGNOR-280178

P62140

P29474

1

dephosphorylation

up-regulates activity

0.2

The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation

SIGNOR-248574

Q13469

Q86Y07

0

phosphorylation

up-regulates

0.369

We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain.

SIGNOR-199263

Q9HCK8

P11137

1

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268916

P25815

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.292

S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.

SIGNOR-272919

Q9Y4G8

P46934

0

ubiquitination

down-regulates quantity

0.401

In line with the previous result (XREF_FIG), overexpression of NEDD4-1 reduced the level of CNrasGEF significantly (XREF_FIG).|NEDD4-1 ubiquitinates CNrasGEF in glioma cells.

SIGNOR-278705

P25098

Q16539

1

phosphorylation

down-regulates

0.2

Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates

SIGNOR-150152

P11802

P23760

1

phosphorylation

up-regulates activity

0.296

In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro .

SIGNOR-278512

P04637

P21675

0

phosphorylation

down-regulates

0.681

Phosphorylation on thr-55 by taf1 mediates degradation of p53

SIGNOR-123651

P60983

P17612

0

phosphorylation

up-regulates activity

0.307

Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82.

SIGNOR-249983

O94826

Q13627

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of TOM70 Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase.

SIGNOR-279994

Q14493

Q6FI13

1

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265396

Q9P212

P01112

1

guanine nucleotide exchange factor

up-regulates

0.578

The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp.

SIGNOR-82859

Q93084

P14921

0

transcriptional regulation

up-regulates quantity by expression

0.326

Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold.

SIGNOR-261601

P35240

Q9UKE5

0

phosphorylation

up-regulates activity

0.2

Consistently with TNIK modulating Merlin, we also observed reduced YAP levels following TNIK knockdown in LK2 and NCI-H520 cells (Supplementary Fig. S7B).|Using in vitro kinase assays followed by phosphopeptide mapping, and mass spectrometry analysis on Merlin isolated from cells co-expressing TNIK and Merlin, we determined that TNIK could phosphorylate Merlin at S13, T272, S315, and T576 (Fig. 4B, Supplementary Fig. S4D, and Supplementary Table S3).

SIGNOR-278386

O43307

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.834

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-260534

P68400

P30519

1

phosphorylation

up-regulates activity

0.335

Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2

SIGNOR-250895

P54132

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.259

We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.

SIGNOR-276906

Q9Y618

P10275

1

acetylation

down-regulates

0.562

In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.

SIGNOR-101286

O43490

Q15262

0

dephosphorylation

down-regulates activity

0.2

PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo.

SIGNOR-277133

O96017

Q14457

1

phosphorylation

up-regulates activity

0.299

We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration

SIGNOR-264557

P32929

Q13237

0

phosphorylation

down-regulates activity

0.244

CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) of CSE, inhibiting the production of H2S.

SIGNOR-275800

P41240

Q96J02

1

phosphorylation

down-regulates activity

0.2

CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro.

SIGNOR-245327

Q13469

P16298

0

dephosphorylation

up-regulates

0.614

Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.

SIGNOR-233438

P78368

P07948

1

phosphorylation

up-regulates quantity by stabilization

0.2

Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.

SIGNOR-275397

Q9HAW4

Q9UKB1

0

ubiquitination

down-regulates

0.345

Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase.

SIGNOR-148438

Q16539

P04150

1

phosphorylation

up-regulates

0.511

We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.

SIGNOR-135198

Q6R6M4

Q99538

1

deubiquitination

down-regulates quantity by destabilization

0.309

We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation.

SIGNOR-272854

Q7Z6J0

P31751

0

phosphorylation

down-regulates

0.389

Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac

SIGNOR-155233

Q86WV6

Q99942

0

ubiquitination

down-regulates quantity by destabilization

0.2

The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection.

SIGNOR-271484

O60381

Q16539

0

phosphorylation

up-regulates

0.43

A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.

SIGNOR-119138

Q9H4G4

P51617

0

phosphorylation

up-regulates activity

0.325

We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion.

SIGNOR-262887

Q00535

P07814

1

phosphorylation

down-regulates

0.2

Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation

SIGNOR-187383

Q13043

P10275

1

phosphorylation

down-regulates activity

0.2

Here we showed that MST1 is an androgen receptor kinase and phosphorylates androgen receptor at Ser-650 ( ).|Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter.

SIGNOR-280143

Q9BRK5

Q8IXL6

0

phosphorylation

up-regulates activity

0.2

Together, these results indicate that Fam20C kinase activity drives the sorting and secretion of the Cab45 dependent client LyzC.|We show that Fam20C phosphorylates Cab45 on distinct residues and thereby decreases Cab45 retention in the TGN.

SIGNOR-279330

Q99942

O43511

1

ubiquitination

down-regulates quantity by destabilization

0.2

E3 ubiquitin ligase Rma1 is involved in Pendrin degradation

SIGNOR-271497

P53350

O43663

1

phosphorylation

down-regulates activity

0.723

Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase.

SIGNOR-279645

O43497

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.261

Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression.

SIGNOR-264034

P35813

P46937

1

dephosphorylation

up-regulates activity

0.269

Although the authors show an in vitro kinase assay where PPM1A supposedly dephosphorylates YAP on Ser127, Fig. 4A lacks a positive control to ensure that PPM1A purified from cells is active.|The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.

SIGNOR-276984

P54764

P51692

1

phosphorylation

up-regulates activity

0.375

We have shown here that EphA4 can phosphorylate STAT5B, but it is not yet clear whether the nuclear translocation of phosphorylated STAT5B is enhanced by EphA4.

SIGNOR-278934

Q504Q3

Q13315

0

phosphorylation

up-regulates activity

0.2

Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52.

SIGNOR-273508

P05771-2

P62714

0

dephosphorylation

down-regulates activity

0.469

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248587

Q9C0B5

Q15910

1

palmitoylation

down-regulates activity

0.2

Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2.

SIGNOR-261144

P23588

P31749

0

phosphorylation

up-regulates

0.393

Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b.

SIGNOR-252520

Q14938

P54764

1

transcriptional regulation

up-regulates quantity

0.2

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268908

P40763

P22455

0

phosphorylation

up-regulates activity

0.402

Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.

SIGNOR-251142

P61586

Q8IW93

0

guanine nucleotide exchange factor

up-regulates activity

0.636

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-260543

P40763

P22607

0

phosphorylation

up-regulates activity

0.631

Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.

SIGNOR-251139

Q15796

P27037

0

phosphorylation

up-regulates activity

0.71

In ACVR2A/B dKO parental cells, only ACVR2A , but not ACVR2A , could rescue both pSMAD2 and pSMAD1/5 (Fig\u00a04B).|In marked contrast, in ACVR2A/B dKO HOM1 cells, ACVR2A restored SMAD1/5 phosphorylation, but not SMAD2 phosphorylation (Fig\u00a04C).

SIGNOR-279786

P11387

P78527

0

phosphorylation

down-regulates quantity by destabilization

0.448

Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.

SIGNOR-277352

P15172

P08047

1

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

P49841

Q13541

1

phosphorylation

down-regulates activity

0.364

We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation.

SIGNOR-236026

Q92879

P31749

0

phosphorylation

up-regulates activity

0.41

In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA.

SIGNOR-280173

Q96AX9

Q9Y219

1

ubiquitination

up-regulates

0.809

Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.

SIGNOR-137922

P49757

Q6PML9

0

ubiquitination

down-regulates quantity by destabilization

0.2

Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation.

SIGNOR-113704

P31749

P67809

1

phosphorylation

up-regulates

0.558

Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102

SIGNOR-252521

P17252

P06127

1

phosphorylation

up-regulates

0.339

Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.

SIGNOR-85179

P41743

Q92934

1

phosphorylation

down-regulates

0.32

In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer

SIGNOR-172894

Q13393

P17252

0

phosphorylation

up-regulates

0.714

Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.

SIGNOR-69938

Q96RU2

Q9HA47

1

deubiquitination

up-regulates quantity by stabilization

0.2

We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.

SIGNOR-275855

O60674

Q92858

1

phosphorylation

up-regulates quantity

0.339

We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling.

SIGNOR-262201

P43146

O00555

1

null

up-regulates activity

0.2

DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.

SIGNOR-268293

P05067

P06241

0

phosphorylation

up-regulates quantity

0.451

Fyn induced phosphorylation of APP at Tyr-757 of the (757)YENPTY(762) motif and increased cell surface expression of APP.

SIGNOR-278378

Q15759

P15923

1

phosphorylation

up-regulates

0.436

Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription, while the nonphosphorylatable e47 mutant ser140ala fails to heterodimerize with myod and displays impaired myogenic potentia

SIGNOR-134190

P06493

P35251

1

phosphorylation

down-regulates activity

0.245

Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. |Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA.

SIGNOR-265504

O14939

P00533

0

phosphorylation

up-regulates activity

0.516

Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold

SIGNOR-251095

P29590

P06493

0

phosphorylation

down-regulates

0.345

Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation.

SIGNOR-176033

Q08881

Q8TDQ0

1

phosphorylation

up-regulates activity

0.31

When we tested the effect of ITK on the Y265 mutant, we found a pronounced reduction of ITK-mediated tyrosine phosphorylation, suggesting that Y265 is specifically phosphorylated by ITK (Fig. 3B). Our results demonstrate that specific phosphorylation of Y265 of Tim-3 occurs in the presence of galectin-9, probably through a receptor-ligand interaction. Phosphorylation of Y265, which is situated in a highly conserved SH2 binding domain, could result in the recruitment of SH2 containing adaptor proteins and trigger downstream signalling events regulating the fate of Tim-3 expressing T-cells.

SIGNOR-273644

P37275

Q13315

0

phosphorylation

up-regulates activity

0.474

Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation.|Therefore, ATM dependent phosphorylation of ZEB1 at S585 is crucial for IR induced stabilization of ZEB1 but not the interaction between ZEB1 and USP7.

SIGNOR-278329

Q01130

Q00987

1

transcriptional regulation

up-regulates quantity by expression

0.279

Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2.

SIGNOR-260076

Q00535

P27695

1

phosphorylation

up-regulates activity

0.377

Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5.

SIGNOR-276337

Q9BZI1

P27361

0

phosphorylation

up-regulates activity

0.2

To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target.

SIGNOR-263061

Q99683

Q5S007

0

phosphorylation

up-regulates activity

0.325

LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site.

SIGNOR-277251

O96013

O94806

0

phosphorylation

up-regulates activity

0.252

PAK4 activity is regulated by an autoinhibitory domain that is released upon RhoGTPase binding as well as phosphorylation at Ser474 in the activation loop of the kinase domain. In the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1)

SIGNOR-275931

P18031

P35222

1

dephosphorylation

up-regulates activity

0.66

PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.

SIGNOR-277121

P14373

O00750

1

ubiquitination

down-regulates

0.402

We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity.

SIGNOR-177935

O60674

Q6N021

1

phosphorylation

up-regulates activity

0.418

Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.

SIGNOR-277289

Q8IYT8

P09467

1

phosphorylation

down-regulates activity

0.2

Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).

SIGNOR-274039

P01106

P56178

0

transcriptional regulation

up-regulates quantity

0.274

Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells

SIGNOR-241914

Q9H1R3

Q06413

1

phosphorylation

up-regulates activity

0.402

Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.

SIGNOR-238118

P27361

Q13153

1

phosphorylation

down-regulates

0.337

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

SIGNOR-123074

P41279

Q02750

1

phosphorylation

up-regulates

0.574

Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf

SIGNOR-36453

O43324

Q05086

0

ubiquitination

down-regulates quantity

0.2

These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling.

SIGNOR-278680

P68400

O43889

1

phosphorylation

down-regulates quantity by destabilization

0.2

Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3.

SIGNOR-277501

P68400

O60341

1

phosphorylation

up-regulates activity

0.318

We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.

SIGNOR-276903

P49841

P12931

1

phosphorylation

up-regulates activity

0.383

P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity.

SIGNOR-278444

Q9UER7

Q13315

0

phosphorylation

down-regulates

0.499

The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation.

SIGNOR-200889

Q9UPX8

O95886

0

relocalization

up-regulates activity

0.788

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

SIGNOR-264593

Q13191

O00459

1

ubiquitination

down-regulates activity

0.499

Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. it can be postulated that Cbl-b, as an E3 Ub ligase, may play a general role in functional regulation of its target proteins through ubiquitination in a protein degradation-independent manner.

SIGNOR-271424

Q2M1Z3

P63000

1

gtpase-activating protein

down-regulates activity

0.566

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-260489

Q68EM7

P17612

0

phosphorylation

down-regulates activity

0.2

Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex.

SIGNOR-272155

Q92733

Q9UI95

1

relocalization

up-regulates

0.496

We found that the human papillary renal cell carcinoma-associated proteinprccinteracts with the cell cycle control proteinmad2b, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function.

SIGNOR-126516

Q53ET0

Q9H0K1

0

phosphorylation

down-regulates

0.743

Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2

SIGNOR-142218

P27986

Q15139

0

phosphorylation

up-regulates activity

0.2

PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration.

SIGNOR-276426

P35813

Q15796

1

dephosphorylation

down-regulates

0.668

Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.

SIGNOR-146919

Q96CW1

P00533

1

relocalization

down-regulates

0.524

The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr.

SIGNOR-185124