GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q5S007	Q99962	1	phosphorylation	down-regulates	0.472	We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75.	SIGNOR-192072
P10070	P17612	0	phosphorylation	down-regulates	0.468	In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation	SIGNOR-154273
P49407	P12931	0	phosphorylation	down-regulates	0.684	Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.	SIGNOR-154564
P27361	P36507	0	phosphorylation	up-regulates	0.742	The primary structure of mek, a protein kinase that phosphorylates the erk gene product	SIGNOR-19244
Q5S007	O43353	1	phosphorylation	up-regulates activity	0.376	Altogether, our results indicate a scenario that LRRK2 physically interacts with Rip2 and promotes phosphorylation of Rip2.\|Taken together, our results show that LRRK2 enhances Rip2 activity by promoting the phosphorylation of Rip2 at Ser176.	SIGNOR-278953
P00533	P48431	1	phosphorylation	up-regulates quantity by stabilization	0.48	These data indicate that EGFR\u2010induced SOX2 Tyr277 phosphorylation prevents the autophagic degradation of SOX2 and enhances its stability.	SIGNOR-279036
P00519	O60260	1	phosphorylation	down-regulates	0.2	Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function.	SIGNOR-167853
Q9Y2K2	P56524	1	phosphorylation	down-regulates activity	0.411	They find that SIK3 phosphorylates and inhibits HDAC4 during feeding states.\|They find that SIK3 phosphorylates and inhibits HDAC4 during feeding\nstates.	SIGNOR-279430
Q13243	Q9HCE7	0	ubiquitination	down-regulates quantity by destabilization	0.262	K125 was also the major site of SRSF5 ubiquitylation mediated by Smurf1.\|Smurf1 targets SRSF5 for degradation upon low glucose	SIGNOR-278665
P05771	P56537	1	phosphorylation	down-regulates activity	0.307	Our results show that release of eIF6 from 60S subunits may operate, in mammalian cells, through a RACK1–PKC betaII pathway. \|Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. \|S235A eIF6 inhibits ribosomal joining in the presence of RACK1–PKCbetaII	SIGNOR-249245
P17252	P35368	1	phosphorylation	down-regulates activity	0.39	Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.	SIGNOR-248988
P60953	Q5TG30	0	gtpase-activating protein	down-regulates activity	0.41	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-260497
P0DPK2	Q92831	0	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269614
O76050	Q8NE35	1	ubiquitination	up-regulates activity	0.47	If Neurl1 interacts and modulates the activity of CPEB3 and increases the translation of GluA1 and GluA2 mRNAs, this effect would be blocked if we abolished the interaction between CPEB3 and Neurl1.\|Neurl1 Interacts with and Ubiquitinates a Translational Regulator of GluA1 and GluA2 : the Cytoplasmic Polyadenylation Element Binding Protein 3.	SIGNOR-278588
P30304	Q15418	0	phosphorylation	down-regulates	0.366	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-202117
P35125	P62330	1	relocalization	up-regulates	0.66	Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs).	SIGNOR-130019
Q99638	Q13315	0	phosphorylation	up-regulates activity	0.767	Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation.	SIGNOR-105243
P45984	Q13469	1	phosphorylation	down-regulates	0.541	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin	SIGNOR-118223
P13807	Q13627	0	phosphorylation	down-regulates activity	0.267	DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity.	SIGNOR-260632
P63104	P45984	0	phosphorylation	down-regulates	0.2	Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188	SIGNOR-124031
Q6NZ36	P49841	0	phosphorylation	down-regulates quantity	0.2	Furthermore, GSK3beta was able to decrease the cellular FAAP20 levels when overexpressed in wild-type, but not in FBW7 -/- HCT116 cells, indicating that GSK3beta requires downstream FBW7 to regulate the FAAP20 stability.\|GSK3\u03b2 phosphorylates FAAP20 at Ser113.	SIGNOR-279048
Q13469	P45984	0	phosphorylation	down-regulates	0.541	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin	SIGNOR-118223
Q53ET0	Q13131	0	phosphorylation	down-regulates	0.544	Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation	SIGNOR-176426
P00533	O14939	1	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
Q99808	Q05655	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1	SIGNOR-260888
Q92793	Q9UBE8	0	phosphorylation	up-regulates activity	0.557	In vitro kinase assay showed that NLK could phosphorylate the C-terminal domain of CBP.	SIGNOR-280048
P41182	P28482	0	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
O60229	Q16659	0	phosphorylation	up-regulates activity	0.406	The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements.	SIGNOR-263094
Q9UJV9	P19474	0	ubiquitination	down-regulates quantity	0.638	Furthermore, overexpression of TRIM21 in mDCs led to lower expression of DDX41 in these mDCs and up to 70% less IFN-beta production by mDCs in response to intracellular DNA (XREF_FIG).\|Here we report that the E3 ligase TRIM21 negatively regulated the type I interferon response in myeloid dendritic cells (mDCs) and monocytes that had been induced by cytosolic double stranded DNA (dsDNA), mainly by promoting the ubiquitination and degradation of DDX41.	SIGNOR-278790
Q14393	Q14938	0	transcriptional regulation	down-regulates quantity	0.205	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268888
P29475	Q9UQM7	0	phosphorylation	down-regulates activity	0.471	It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.	SIGNOR-250635
P10415	P17252	0	phosphorylation	up-regulates	0.349	Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70	SIGNOR-60120
Q99453	Q96F44	0	ubiquitination	down-regulates	0.485	The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.	SIGNOR-195878
P48729	P37840	1	phosphorylation	up-regulates	0.371	In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.	SIGNOR-73799
P06401	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.277	Here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability.	SIGNOR-276498
P04637	O15151	0	ubiquitination	down-regulates quantity by destabilization	0.948	Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.	SIGNOR-271389
Q6U7Q0	Q969H0	0	ubiquitination	down-regulates quantity by destabilization	0.2	CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction.	SIGNOR-264898
Q00534	P46527	1	phosphorylation	up-regulates	0.855	Phosphorylation on ser-10 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.p27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization.	SIGNOR-140401
Q12824	Q96EP1	0	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
P07288	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.2	We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA.	SIGNOR-253664
P42345	P06730	1	phosphorylation	down-regulates activity	0.801	Mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates and inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1).	SIGNOR-278963
Q99801	Q13315	0	phosphorylation	down-regulates quantity by destabilization	0.362	ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction.	SIGNOR-276499
P15172	P06493	0	phosphorylation	down-regulates	0.364	Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.	SIGNOR-121601
P0DTC2	P07711	0	cleavage	up-regulates activity	0.2	SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.	SIGNOR-260737
P06400	Q00534	0	phosphorylation	down-regulates	0.769	Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively.	SIGNOR-135189
Q8IVL1	Q9ULU4	0	transcriptional regulation	up-regulates quantity by expression	0.2	We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.	SIGNOR-266209
Q96GD4	Q99661	1	phosphorylation	up-regulates	0.731	Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.	SIGNOR-155890
Q9NWZ3	P14598	1	phosphorylation	up-regulates	0.38	Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation.	SIGNOR-152027
Q9Y6K9	P07948	0	phosphorylation	down-regulates activity	0.357	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-276369
Q9UN37	O43633	1	cleavage	up-regulates activity	0.911	Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.	SIGNOR-260846
O75791	Q92918	0	phosphorylation	down-regulates activity	0.834	Serine/threonine phosphorylation of the T cell adaptor proteins SLP76 and GADS by HPK1 induces their release from signaling microclusters and subsequent termination of the T cell response.	SIGNOR-279421
Q15831	P25116	1	phosphorylation	up-regulates activity	0.2	LKB1 phosphorylates PAR-1 at the T408 site xref .\|LKB1 thus positively regulates PAR-1 at the postsynapse.	SIGNOR-278992
P17612	Q00536	1	phosphorylation	down-regulates	0.314	Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site.	SIGNOR-191623
Q9UPS6	P68431	1	methylation	down-regulates activity	0.2	SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.	SIGNOR-265576
O00141	P51608	0	transcriptional regulation	down-regulates quantity by repression	0.292	These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.	SIGNOR-264543
Q12929	Q13882	0	phosphorylation	up-regulates activity	0.357	Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis.	SIGNOR-263191
Q00535	Q8IWU2	1	phosphorylation	up-regulates	0.497	Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __	SIGNOR-195329
P06241	Q96PD2	1	phosphorylation	up-regulates activity	0.35	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273946
Q16665	Q6ZMT4	1	transcriptional regulation	up-regulates quantity by expression	0.2	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271572
Q96SN8	Q96MT8	1	relocalization	up-regulates activity	0.692	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271722
P24723	O15530	0	phosphorylation	up-regulates activity	0.316	Protein kinase C(eta) is phosphorylated by PDK1 in vitro, leading to kinase activation as similarly reported for protein kinase C(epsilon) activation by PDK1.	SIGNOR-280062
Q13153	P27694	1	phosphorylation	up-regulates activity	0.2	In this article, we found that Ser-135 and Thr-180 of RPA1 are directly phosphorylated by PAK1 in a DOCK7-Rac1/Cdc42-dependent manner.\|We further explored the biological role of PAK1 in replication stress and found that depletion of PAK1 resulted in decreased RPA1 and RPA2 chromatin loading and RPA2 foci formation ( Figure 4I-K ) .	SIGNOR-279378
Q01860	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.303	CHIP overexpression decreased OCT4 stability through proteasomal degradation.\|CHIP E3 ligase ubiquitinates OCT4 at lysine 284.\|These data suggest that CHIP induces OCT4 ubiquitination and degradation.	SIGNOR-278562
Q00535	O43464	1	phosphorylation	up-regulates	0.456	Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress	SIGNOR-174598
P27361	P24928	1	phosphorylation	down-regulates	0.316	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120176
P31751	P24666	0	dephosphorylation	down-regulates activity	0.2	Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.\|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3	SIGNOR-248456
P46934	O43597	1	polyubiquitination	down-regulates quantity by destabilization	0.39	Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability.	SIGNOR-271425
O15264	P10636	1	phosphorylation	down-regulates activity	0.531	Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in the ability of tau to promote microtubule assembly.	SIGNOR-278313
P50613	P06493	1	phosphorylation	up-regulates	0.581	The mo15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (cdks) through phosphorylation of thr161 and its homologues	SIGNOR-38307
P10588	Q05655	0	phosphorylation	down-regulates	0.2	Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.	SIGNOR-180017
P62136	P08047	1	dephosphorylation	down-regulates activity	0.266	Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.	SIGNOR-251952
Q16584	P06493	0	phosphorylation	down-regulates activity	0.2	Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases.	SIGNOR-277603
P06493	P30260	1	phosphorylation	up-regulates	0.704	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119873
Q05195	P23443	0	phosphorylation	down-regulates	0.304	Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc.	SIGNOR-178590
Q8TAM6	O95096	0	transcriptional regulation	up-regulates quantity by expression	0.249	Further study revealed that Nkx2.2 could bind JN promoter and its overexpression increase the promoter activity of JN.	SIGNOR-268965
Q14653	P35813	0	dephosphorylation	down-regulates activity	0.247	In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).\|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG).	SIGNOR-277152
P04629	P18031	0	dephosphorylation	down-regulates activity	0.378	PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a " gate-keeper " mechanism that ensures targeting of inactive receptors to axons to engage with ligand.\|We identify a gate keeping mechanism in which TrkA receptors, destined for transcytosis, are dephosphorylated in neuronal soma by the ER-resident tyrosine phosphatase, PTP1B.	SIGNOR-277081
P57737	P12931	0	phosphorylation	up-regulates activity	0.339	We establish that Src activity is indispensable for the interaction of Crn7 with Golgi membranes. Crn7 binds Src in vivo and can be phosphorylated by recombinant Src in vitro. We demonstrate that tyrosine-758 is the major Src phosphorylation site.	SIGNOR-274005
P61586	P52735	0	guanine nucleotide exchange factor	up-regulates activity	0.75	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-260582
Q9Y458	P35548	1	transcriptional regulation	down-regulates quantity by repression	0.309	the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.	SIGNOR-265567
P30989	P34947	0	phosphorylation	up-regulates activity	0.594	Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively.	SIGNOR-278234
P55211	Q05513	0	phosphorylation	down-regulates	0.348	Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta).	SIGNOR-141629
P05771	P17302	1	phosphorylation	down-regulates activity	0.388	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.\|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249049
P60604	Q86TM6	1	ubiquitination	up-regulates activity	0.659	We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.	SIGNOR-272593
Q13761	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.579	RUNX3 protein is ubiquitinated by MDM2 at Lys-94 and Lys-148.\|RUNX3 protein is ubiquitinated by MDM2 at Lys 94 and Lys 148.\|MDM2 suppresses the transcriptional activity of RUNX3.	SIGNOR-278557
Q16654	P29803	1	phosphorylation	down-regulates	0.547	Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form	SIGNOR-121936
P28482	P00533	1	phosphorylation	down-regulates activity	0.639	A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase	SIGNOR-20545
P01112	Q07889	0	guanine nucleotide exchange factor	up-regulates activity	0.892	The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras.	SIGNOR-59472
Q9P107	P61586	1	gtpase-activating protein	down-regulates activity	0.643	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-260505
P00533	Q8ND25	1	phosphorylation	up-regulates activity	0.27	Together, these results demonstrate that EGFR-dependent phosphorylation of ZNRF1 at Y103 promotes degradation of AKT and resultant activation of GSK3\u03b2, which mediates oxidative stress\u2013induced neuronal apoptosis ( xref ).	SIGNOR-279522
P31749	P15559	1	phosphorylation	down-regulates quantity by destabilization	0.369	Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.	SIGNOR-276868
Q9UBE8	Q9UJU2	1	phosphorylation	down-regulates	0.76	Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.	SIGNOR-97812
P11233	P98177	1	phosphorylation	up-regulates activity	0.2	We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT.	SIGNOR-249665
Q16539	P06241	0	phosphorylation	up-regulates	0.489	T cell src family kinases and zap70 activate p38 by phosphorylating tyr323.	SIGNOR-134293
P19438	P28482	0	phosphorylation	down-regulates activity	0.5	Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.\|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a	SIGNOR-249453
Q9ULT6	Q2MKA7	0	relocalization	down-regulates quantity	0.803	Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3.	SIGNOR-260113
Q02078	Q15759	0	phosphorylation	up-regulates activity	0.533	In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.	SIGNOR-280024
P12931	P19404	1	phosphorylation	up-regulates activity	0.322	Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants.	SIGNOR-276419
Q00535	Q15303	1	phosphorylation	up-regulates activity	0.278	Cdk5 Promotes ErbB4 and PI3-Kinase Activity In Vivo.\|Cdk5 phosphorylates ErbB4 at T1152, situated in close proximity to the PI3-kinase-binding site (Y1056), and in turn promotes ErbB4 tyrosine phosphorylation.	SIGNOR-278436
Q05513	P47712	1	phosphorylation	up-regulates activity	0.327	To further evaluate cPLA2 as a candidate substrate for PKCζ, we developed a custom antibody recognizing the cPLA2 T376 phosphorylation site. Specificity was validated in both serum starved/stimulated samples	SIGNOR-277518

Q5S007

Q99962

1

phosphorylation

down-regulates

0.472

We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75.

SIGNOR-192072

P10070

P17612

0

phosphorylation

down-regulates

0.468

In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation

SIGNOR-154273

P49407

P12931

0

phosphorylation

down-regulates

0.684

Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.

SIGNOR-154564

P27361

P36507

0

phosphorylation

up-regulates

0.742

The primary structure of mek, a protein kinase that phosphorylates the erk gene product

SIGNOR-19244

Q5S007

O43353

1

phosphorylation

up-regulates activity

0.376

Altogether, our results indicate a scenario that LRRK2 physically interacts with Rip2 and promotes phosphorylation of Rip2.|Taken together, our results show that LRRK2 enhances Rip2 activity by promoting the phosphorylation of Rip2 at Ser176.

SIGNOR-278953

P00533

P48431

1

phosphorylation

up-regulates quantity by stabilization

0.48

These data indicate that EGFR\u2010induced SOX2 Tyr277 phosphorylation prevents the autophagic degradation of SOX2 and enhances its stability.

SIGNOR-279036

P00519

O60260

1

phosphorylation

down-regulates

0.2

Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function.

SIGNOR-167853

Q9Y2K2

P56524

1

phosphorylation

down-regulates activity

0.411

They find that SIK3 phosphorylates and inhibits HDAC4 during feeding states.|They find that SIK3 phosphorylates and inhibits HDAC4 during feeding\nstates.

SIGNOR-279430

Q13243

Q9HCE7

0

ubiquitination

down-regulates quantity by destabilization

0.262

K125 was also the major site of SRSF5 ubiquitylation mediated by Smurf1.|Smurf1 targets SRSF5 for degradation upon low glucose

SIGNOR-278665

P05771

P56537

1

phosphorylation

down-regulates activity

0.307

Our results show that release of eIF6 from 60S subunits may operate, in mammalian cells, through a RACK1–PKC betaII pathway. |Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. |S235A eIF6 inhibits ribosomal joining in the presence of RACK1–PKCbetaII

SIGNOR-249245

P17252

P35368

1

phosphorylation

down-regulates activity

0.39

Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.

SIGNOR-248988

P60953

Q5TG30

0

gtpase-activating protein

down-regulates activity

0.41

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-260497

P0DPK2

Q92831

0

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269614

O76050

Q8NE35

1

ubiquitination

up-regulates activity

0.47

If Neurl1 interacts and modulates the activity of CPEB3 and increases the translation of GluA1 and GluA2 mRNAs, this effect would be blocked if we abolished the interaction between CPEB3 and Neurl1.|Neurl1 Interacts with and Ubiquitinates a Translational Regulator of GluA1 and GluA2 : the Cytoplasmic Polyadenylation Element Binding Protein 3.

SIGNOR-278588

P30304

Q15418

0

phosphorylation

down-regulates

0.366

Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.

SIGNOR-202117

P35125

P62330

1

relocalization

up-regulates

0.66

Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs).

SIGNOR-130019

Q99638

Q13315

0

phosphorylation

up-regulates activity

0.767

Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation.

SIGNOR-105243

P45984

Q13469

1

phosphorylation

down-regulates

0.541

Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin

SIGNOR-118223

P13807

Q13627

0

phosphorylation

down-regulates activity

0.267

DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity.

SIGNOR-260632

P63104

P45984

0

phosphorylation

down-regulates

0.2

Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188

SIGNOR-124031

Q6NZ36

P49841

0

phosphorylation

down-regulates quantity

0.2

Furthermore, GSK3beta was able to decrease the cellular FAAP20 levels when overexpressed in wild-type, but not in FBW7 -/- HCT116 cells, indicating that GSK3beta requires downstream FBW7 to regulate the FAAP20 stability.|GSK3\u03b2 phosphorylates FAAP20 at Ser113.

SIGNOR-279048

Q13469

P45984

0

phosphorylation

down-regulates

0.541

Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin

SIGNOR-118223

Q53ET0

Q13131

0

phosphorylation

down-regulates

0.544

Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation

SIGNOR-176426

P00533

O14939

1

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

Q99808

Q05655

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1

SIGNOR-260888

Q92793

Q9UBE8

0

phosphorylation

up-regulates activity

0.557

In vitro kinase assay showed that NLK could phosphorylate the C-terminal domain of CBP.

SIGNOR-280048

P41182

P28482

0

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

O60229

Q16659

0

phosphorylation

up-regulates activity

0.406

The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements.

SIGNOR-263094

Q9UJV9

P19474

0

ubiquitination

down-regulates quantity

0.638

Furthermore, overexpression of TRIM21 in mDCs led to lower expression of DDX41 in these mDCs and up to 70% less IFN-beta production by mDCs in response to intracellular DNA (XREF_FIG).|Here we report that the E3 ligase TRIM21 negatively regulated the type I interferon response in myeloid dendritic cells (mDCs) and monocytes that had been induced by cytosolic double stranded DNA (dsDNA), mainly by promoting the ubiquitination and degradation of DDX41.

SIGNOR-278790

Q14393

Q14938

0

transcriptional regulation

down-regulates quantity

0.205

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268888

P29475

Q9UQM7

0

phosphorylation

down-regulates activity

0.471

It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.

SIGNOR-250635

P10415

P17252

0

phosphorylation

up-regulates

0.349

Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70

SIGNOR-60120

Q99453

Q96F44

0

ubiquitination

down-regulates

0.485

The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.

SIGNOR-195878

P48729

P37840

1

phosphorylation

up-regulates

0.371

In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.

SIGNOR-73799

P06401

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.277

Here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability.

SIGNOR-276498

P04637

O15151

0

ubiquitination

down-regulates quantity by destabilization

0.948

Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.

SIGNOR-271389

Q6U7Q0

Q969H0

0

ubiquitination

down-regulates quantity by destabilization

0.2

CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction.

SIGNOR-264898

Q00534

P46527

1

phosphorylation

up-regulates

0.855

Phosphorylation on ser-10 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.p27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization.

SIGNOR-140401

Q12824

Q96EP1

0

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

P07288

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.2

We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA.

SIGNOR-253664

P42345

P06730

1

phosphorylation

down-regulates activity

0.801

Mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates and inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1).

SIGNOR-278963

Q99801

Q13315

0

phosphorylation

down-regulates quantity by destabilization

0.362

ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction.

SIGNOR-276499

P15172

P06493

0

phosphorylation

down-regulates

0.364

Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.

SIGNOR-121601

P0DTC2

P07711

0

cleavage

up-regulates activity

0.2

SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.

SIGNOR-260737

P06400

Q00534

0

phosphorylation

down-regulates

0.769

Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively.

SIGNOR-135189

Q8IVL1

Q9ULU4

0

transcriptional regulation

up-regulates quantity by expression

0.2

We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.

SIGNOR-266209

Q96GD4

Q99661

1

phosphorylation

up-regulates

0.731

Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.

SIGNOR-155890

Q9NWZ3

P14598

1

phosphorylation

up-regulates

0.38

Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation.

SIGNOR-152027

Q9Y6K9

P07948

0

phosphorylation

down-regulates activity

0.357

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-276369

Q9UN37

O43633

1

cleavage

up-regulates activity

0.911

Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.

SIGNOR-260846

O75791

Q92918

0

phosphorylation

down-regulates activity

0.834

Serine/threonine phosphorylation of the T cell adaptor proteins SLP76 and GADS by HPK1 induces their release from signaling microclusters and subsequent termination of the T cell response.

SIGNOR-279421

Q15831

P25116

1

phosphorylation

up-regulates activity

0.2

LKB1 phosphorylates PAR-1 at the T408 site xref .|LKB1 thus positively regulates PAR-1 at the postsynapse.

SIGNOR-278992

P17612

Q00536

1

phosphorylation

down-regulates

0.314

Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site.

SIGNOR-191623

Q9UPS6

P68431

1

methylation

down-regulates activity

0.2

SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.

SIGNOR-265576

O00141

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.292

These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.

SIGNOR-264543

Q12929

Q13882

0

phosphorylation

up-regulates activity

0.357

Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis.

SIGNOR-263191

Q00535

Q8IWU2

1

phosphorylation

up-regulates

0.497

Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __

SIGNOR-195329

P06241

Q96PD2

1

phosphorylation

up-regulates activity

0.35

Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.

SIGNOR-273946

Q16665

Q6ZMT4

1

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-271572

Q96SN8

Q96MT8

1

relocalization

up-regulates activity

0.692

Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.

SIGNOR-271722

P24723

O15530

0

phosphorylation

up-regulates activity

0.316

Protein kinase C(eta) is phosphorylated by PDK1 in vitro, leading to kinase activation as similarly reported for protein kinase C(epsilon) activation by PDK1.

SIGNOR-280062

Q13153

P27694

1

phosphorylation

up-regulates activity

0.2

In this article, we found that Ser-135 and Thr-180 of RPA1 are directly phosphorylated by PAK1 in a DOCK7-Rac1/Cdc42-dependent manner.|We further explored the biological role of PAK1 in replication stress and found that depletion of PAK1 resulted in decreased RPA1 and RPA2 chromatin loading and RPA2 foci formation ( Figure 4I-K ) .

SIGNOR-279378

Q01860

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.303

CHIP overexpression decreased OCT4 stability through proteasomal degradation.|CHIP E3 ligase ubiquitinates OCT4 at lysine 284.|These data suggest that CHIP induces OCT4 ubiquitination and degradation.

SIGNOR-278562

Q00535

O43464

1

phosphorylation

up-regulates

0.456

Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress

SIGNOR-174598

P27361

P24928

1

phosphorylation

down-regulates

0.316

Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.

SIGNOR-120176

P31751

P24666

0

dephosphorylation

down-regulates activity

0.2

Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3

SIGNOR-248456

P46934

O43597

1

polyubiquitination

down-regulates quantity by destabilization

0.39

Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability.

SIGNOR-271425

O15264

P10636

1

phosphorylation

down-regulates activity

0.531

Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in the ability of tau to promote microtubule assembly.

SIGNOR-278313

P50613

P06493

1

phosphorylation

up-regulates

0.581

The mo15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (cdks) through phosphorylation of thr161 and its homologues

SIGNOR-38307

P10588

Q05655

0

phosphorylation

down-regulates

0.2

Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.

SIGNOR-180017

P62136

P08047

1

dephosphorylation

down-regulates activity

0.266

Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.

SIGNOR-251952

Q16584

P06493

0

phosphorylation

down-regulates activity

0.2

Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases.

SIGNOR-277603

P06493

P30260

1

phosphorylation

up-regulates

0.704

Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation

SIGNOR-119873

Q05195

P23443

0

phosphorylation

down-regulates

0.304

Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc.

SIGNOR-178590

Q8TAM6

O95096

0

transcriptional regulation

up-regulates quantity by expression

0.249

Further study revealed that Nkx2.2 could bind JN promoter and its overexpression increase the promoter activity of JN.

SIGNOR-268965

Q14653

P35813

0

dephosphorylation

down-regulates activity

0.247

In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG).

SIGNOR-277152

P04629

P18031

0

dephosphorylation

down-regulates activity

0.378

PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a " gate-keeper " mechanism that ensures targeting of inactive receptors to axons to engage with ligand.|We identify a gate keeping mechanism in which TrkA receptors, destined for transcytosis, are dephosphorylated in neuronal soma by the ER-resident tyrosine phosphatase, PTP1B.

SIGNOR-277081

P57737

P12931

0

phosphorylation

up-regulates activity

0.339

We establish that Src activity is indispensable for the interaction of Crn7 with Golgi membranes. Crn7 binds Src in vivo and can be phosphorylated by recombinant Src in vitro. We demonstrate that tyrosine-758 is the major Src phosphorylation site.

SIGNOR-274005

P61586

P52735

0

guanine nucleotide exchange factor

up-regulates activity

0.75

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-260582

Q9Y458

P35548

1

transcriptional regulation

down-regulates quantity by repression

0.309

the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.

SIGNOR-265567

P30989

P34947

0

phosphorylation

up-regulates activity

0.594

Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively.

SIGNOR-278234

P55211

Q05513

0

phosphorylation

down-regulates

0.348

Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta).

SIGNOR-141629

P05771

P17302

1

phosphorylation

down-regulates activity

0.388

Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.

SIGNOR-249049

P60604

Q86TM6

1

ubiquitination

up-regulates activity

0.659

We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.

SIGNOR-272593

Q13761

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.579

RUNX3 protein is ubiquitinated by MDM2 at Lys-94 and Lys-148.|RUNX3 protein is ubiquitinated by MDM2 at Lys 94 and Lys 148.|MDM2 suppresses the transcriptional activity of RUNX3.

SIGNOR-278557

Q16654

P29803

1

phosphorylation

down-regulates

0.547

Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form

SIGNOR-121936

P28482

P00533

1

phosphorylation

down-regulates activity

0.639

A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase

SIGNOR-20545

P01112

Q07889

0

guanine nucleotide exchange factor

up-regulates activity

0.892

The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras.

SIGNOR-59472

Q9P107

P61586

1

gtpase-activating protein

down-regulates activity

0.643

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-260505

P00533

Q8ND25

1

phosphorylation

up-regulates activity

0.27

Together, these results demonstrate that EGFR-dependent phosphorylation of ZNRF1 at Y103 promotes degradation of AKT and resultant activation of GSK3\u03b2, which mediates oxidative stress\u2013induced neuronal apoptosis ( xref ).

SIGNOR-279522

P31749

P15559

1

phosphorylation

down-regulates quantity by destabilization

0.369

Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.

SIGNOR-276868

Q9UBE8

Q9UJU2

1

phosphorylation

down-regulates

0.76

Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.

SIGNOR-97812

P11233

P98177

1

phosphorylation

up-regulates activity

0.2

We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT.

SIGNOR-249665

Q16539

P06241

0

phosphorylation

up-regulates

0.489

T cell src family kinases and zap70 activate p38 by phosphorylating tyr323.

SIGNOR-134293

P19438

P28482

0

phosphorylation

down-regulates activity

0.5

Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a

SIGNOR-249453

Q9ULT6

Q2MKA7

0

relocalization

down-regulates quantity

0.803

Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3.

SIGNOR-260113

Q02078

Q15759

0

phosphorylation

up-regulates activity

0.533

In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.

SIGNOR-280024

P12931

P19404

1

phosphorylation

up-regulates activity

0.322

Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants.

SIGNOR-276419

Q00535

Q15303

1

phosphorylation

up-regulates activity

0.278

Cdk5 Promotes ErbB4 and PI3-Kinase Activity In Vivo.|Cdk5 phosphorylates ErbB4 at T1152, situated in close proximity to the PI3-kinase-binding site (Y1056), and in turn promotes ErbB4 tyrosine phosphorylation.

SIGNOR-278436

Q05513

P47712

1

phosphorylation

up-regulates activity

0.327

To further evaluate cPLA2 as a candidate substrate for PKCζ, we developed a custom antibody recognizing the cPLA2 T376 phosphorylation site. Specificity was validated in both serum starved/stimulated samples

SIGNOR-277518