GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
O60260	Q8IWA4	1	ubiquitination	down-regulates quantity	0.2	Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2. Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy.	SIGNOR-272779
P12931	P25098	1	phosphorylation	up-regulates activity	0.2	Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.	SIGNOR-266305
Q9NRR4	P49841	0	phosphorylation	up-regulates activity	0.278	Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.	SIGNOR-264846
P00533	Q9Y6I3	0	relocalization	down-regulates	0.596	Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr.	SIGNOR-182562
P45985	P45984	1	phosphorylation	up-regulates	0.729	Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)	SIGNOR-197998
O94901	P53350	0	phosphorylation	down-regulates activity	0.453	Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions.	SIGNOR-263098
Q9P1A6	Q9UPX8	1	relocalization	up-regulates activity	0.849	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-264590
P03372	P06239	0	phosphorylation	up-regulates	0.382	On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation.	SIGNOR-55853
F7VJQ1	Q00535	0	phosphorylation	up-regulates quantity	0.332	Cdk5 phosphorylated PrP induces the aggregation of non phosphorylated PrP.\|Together, these results indicate that S43 is a major Cdk5 phosphorylation site in PrP.	SIGNOR-278920
P01133	O14672	0	cleavage	up-regulates activity	0.566	Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin	SIGNOR-259840
Q13017	Q13882	0	phosphorylation	up-regulates	0.2	Breast tumor kinase phosphorylates p190rhogap to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Brk phosphorylates p190 at the y(1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120rasgap (p120). As a consequence, brk stimulates p190 and attenuates p120 functions, leading to rhoa inactivation and ras activation, respectively.	SIGNOR-181452
P10914	Q00987	0	ubiquitination	down-regulates quantity	0.388	HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation.\|IRF-1 ubiquitination by HDM2 is specifically increased during HIV-1 infection in the presence of increasing amounts of Tat and is mediated by the formation of a trimeric complex between Tat, IRF-1, and HDM2, as demonstrated by coimmunoprecipitation analysis (XREF_FIG).	SIGNOR-278590
Q9HD90	Q9HCK8	0	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-268918
P09630	O15550	0	transcriptional regulation	up-regulates quantity by expression	0.26	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260028
Q15139	Q9UQL6	1	phosphorylation	down-regulates activity	0.516	Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes.	SIGNOR-249270
Q96EB6	Q13043	0	phosphorylation	down-regulates activity	0.344	We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.	SIGNOR-279574
Q09472	P52292	1	acetylation	up-regulates	0.357	Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300	SIGNOR-128625
P48058	P05129	0	phosphorylation	up-regulates	0.702	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-97558
P10915	P09238	0	cleavage	down-regulates quantity by destabilization	0.323	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256332
P05198	P49770	0	guanine nucleotide exchange factor	up-regulates activity	0.802	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269125
Q9P275	P04179	1	deubiquitination	up-regulates quantity by stabilization	0.319	Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36\|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life.	SIGNOR-272280
Q969H0	Q9NYY3	0	phosphorylation	down-regulates	0.483	Plk2 regulates centriole duplication through phosphorylation-mediated degradation of fbxw7 (human cdc4).Plk2 phosphorylates fbxw7 on serine 176	SIGNOR-196448
P31749	P49760	1	phosphorylation	up-regulates	0.39	Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva	SIGNOR-167340
P06241	P16885	1	phosphorylation	up-regulates activity	0.575	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249340
Q04656	P08294	1	null	up-regulates activity	0.696	Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide.	SIGNOR-272267
P27361	P17480	1	phosphorylation	down-regulates	0.579	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-112817
Q14653	P52292	0	relocalization	up-regulates activity	0.2	The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F).	SIGNOR-262514
Q13153	Q9H1Y0	1	phosphorylation	up-regulates quantity by stabilization	0.2	Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. \|As PAK1-mediated phosphorylation at residue T101 protects ATG5 from ubiquitination-dependent degradation	SIGNOR-275835
Q15418	P46527	1	phosphorylation	up-regulates activity	0.393	As for other PI3K effectors, RSK1 phosphorylates p27 at T198.\|RSK1 overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, and p27 stability.	SIGNOR-279653
O43432	Q96NX5	0	phosphorylation	up-regulates	0.2	Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii).	SIGNOR-197149
Q9UNN4	P68400	0	phosphorylation	up-regulates activity	0.424	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. \| Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250873
Q15678	P56945	1	dephosphorylation	down-regulates	0.394	We show that p130 crk-associated substrate (p130cas) is a direct substrate of ptpn14 and that ptpn14 specifically regulates p130cas phosphorylation at tyrosine residue 128 (y128) in colorectal cancer (crc) cells. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation	SIGNOR-197923
Q05397	P16591	0	phosphorylation	up-regulates activity	0.251	The Fer mediated phosphorylation of specific tyrosine residues of FAK was abolished by cotransfection of shRNA against Fer (i.e., shFer), but not by control shRNA, indicating that the phosphorylation of Tyr577, 861, or 925 of FAK in suspended cells was indeed caused by Fer.	SIGNOR-279409
P63000	Q68EM7	0	guanine nucleotide exchange factor	up-regulates activity	0.566	ARHGAP17 is a Rho GTPase-activating protein of Rac1	SIGNOR-272166
Q16620	P22001	1	phosphorylation	down-regulates	0.377	Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein.	SIGNOR-183515
Q9P275	P06748	1	deubiquitination	up-regulates quantity by stabilization	0.39	USP36 deubiquitylated the nucleolar proteins nucleophosmin/B23 and fibrillarin, and stabilized them by counteracting ubiquitylation-mediated proteasomal degradation.	SIGNOR-272290
P62140	P31749	1	dephosphorylation	down-regulates activity	0.386	Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells\|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-252604
P16410	P06241	0	phosphorylation	up-regulates quantity by stabilization	0.77	CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4.	SIGNOR-251161
P60484	P19784	0	phosphorylation	down-regulates activity	0.704	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).	SIGNOR-251025
Q9NYV6	P24941	0	phosphorylation	up-regulates	0.508	Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia	SIGNOR-123231
Q2M2I8	Q96CW1	1	phosphorylation	up-regulates	0.79	Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.	SIGNOR-115657
O15217	P0DMV8	0	relocalization	up-regulates activity	0.2	Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. \|Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation	SIGNOR-264799
Q9NQC7	Q14164	0	phosphorylation	down-regulates activity	0.441	CYLD is phosphorylated by IKK\u03b5 at Ser418.\|Together, these observations demonstrate that I\u03baB kinase\u03b5-mediated phosphorylation of CYLD at Ser418 inhibits CYLD deubiquitinase activity.	SIGNOR-278311
P13807	Q96RG2	0	phosphorylation	down-regulates activity	0.508	Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen.	SIGNOR-245866
Q8IYT8	Q9UGI9	1	phosphorylation	down-regulates	0.2	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-173095
Q86WV6	Q9C029	0	ubiquitination	down-regulates quantity by destabilization	0.2	RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation.\|Finally, in vitro ubiquitination assays suggested that RNF90 promoted the ubiquitination of MITA directly (Fig 5E and 5F).	SIGNOR-278678
Q92934	P11309	0	phosphorylation	down-regulates activity	0.371	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250390
P06239	P32119	1	phosphorylation	down-regulates activity	0.2	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276279
P00533	O14964	1	phosphorylation	up-regulates activity	0.637	We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation	SIGNOR-100246
P46531	Q92831	0	acetylation	up-regulates	0.602	In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia.	SIGNOR-199024
P42773	Q13351	0	transcriptional regulation	up-regulates quantity by expression	0.266	Thus, EKLF is a direct regulator of p18INK4c gene expression, and much of EKLF's role in driving erythroid cell differentiation may occur via p18INK4c.	SIGNOR-266046
Q96PU5	Q9NY46	1	ubiquitination	down-regulates quantity by destabilization	0.283	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253464
P40763	Q15262	0	dephosphorylation	down-regulates activity	0.374	In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.\|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705).	SIGNOR-277060
P31994	P07948	0	phosphorylation	up-regulates activity	0.43	Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn	SIGNOR-249380
Q9UEY8	P17252	0	phosphorylation	down-regulates quantity by destabilization	0.334	Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. \| Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. \| The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin	SIGNOR-249143
P18848	Q9UGM6	1	transcriptional regulation	up-regulates quantity by expression	0.246	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269430
P01106	Q96GD4	0	phosphorylation	up-regulates quantity by stabilization	0.373	AURKB directly phosphorylates MYC at serine 67, counteracting GSK3\u03b2-directed threonine 58 phosphorylation and subsequent FBXW7- mediated proteasomal degradation.	SIGNOR-279439
Q96HS1	Q8IVP5	1	dephosphorylation	up-regulates activity	0.627	Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.	SIGNOR-273654
Q9BW19	Q13315	0	phosphorylation	up-regulates quantity by stabilization	0.2	ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.	SIGNOR-277295
Q96PU4	P24864	1	ubiquitination	down-regulates quantity by destabilization	0.332	We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.	SIGNOR-271886
P52630	P23458	0	phosphorylation	up-regulates activity	0.768	STAT2 plays a pivotal role in IFN-a signaling. It is recruited to the activated receptor first and, after phosphorylation by JAK kinases on tyrosine 690, provides a docking site for the SH2 domain of STAT1.	SIGNOR-251344
Q05086	O43166	1	polyubiquitination	down-regulates quantity by destabilization	0.365	the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.	SIGNOR-272608
P49841	P07384	0	cleavage	up-regulates activity	0.297	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251586
P51608	Q9NWB1	1	transcriptional regulation	down-regulates quantity by repression	0.28	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264681
O43318	Q13114	0	ubiquitination	up-regulates activity	0.457	Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.\|TRAF3 activates TAK1 through ubiquitination.	SIGNOR-278787
Q5GLZ8	Q99835	1	ubiquitination	down-regulates quantity by destabilization	0.2	Our data showed that Herc4 mediated Smo degradation by proteasome and lysosome, but mainly by proteasome.\|Using the cell based ubiquitination assay, we found that both Myc-SmoK13R and Myc-SmoK49R exhibited reduced ubiquitination compared with Myc-Smo by Herc4, but Myc-SmoK49R resulted in a more dramatic reduction in Smo ubiquitination (XREF_FIG), suggesting that Smo is ubiquitinated by Herc4 at multiple Lys residues.	SIGNOR-278521
P41162	Q16828	1	transcriptional regulation	down-regulates quantity by repression	0.2	ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation.	SIGNOR-262780
Q13554	Q13224	1	phosphorylation	up-regulates activity	0.606	By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.	SIGNOR-250688
Q96AP0	Q9HC98	0	phosphorylation	up-regulates activity	0.2	NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment\|Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase.\|	SIGNOR-264424
Q86YD1	Q7Z6Z7	0	ubiquitination	down-regulates quantity	0.2	Our data suggest that HUWE1 can ubiquitinate PTOV1 in vitro and depletion of HUWE1 in cells increases the stability of PTOV1 S36A protein in the nucleus.\|Our data suggest that depletion of HUWE1 elevates PTOV1 protein levels, which, in turn, promote the expression of cJun, a pro-growth translational target of PTOV1 (18)\n In our model, we propose that HUWE1 mediates the degradation of PTOV1 in the nucleus.	SIGNOR-278755
Q6J4K2	P17612	0	phosphorylation	up-regulates activity	0.2	However, the PDE2-inhibitory effect is eliminated when the mitochondrial S258A NCLX mutant that mimics a non-PKA phosphorylated state of NCLX is expressed. Altogether, our findings indicate that NCLX is regulated by the mitochondrial PDE2A2 form.\|We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. \|Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site.	SIGNOR-275727
O00429	Q969V5	0	sumoylation	up-regulates activity	0.534	Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.	SIGNOR-274128
P67775	Q13153	1	dephosphorylation	down-regulates activity	0.357	Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248641
P17612	Q15208	1	phosphorylation	down-regulates activity	0.295	GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively. Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.	SIGNOR-276390
Q9BXL7	P67775	0	dephosphorylation	down-regulates activity	0.309	NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane\|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.	SIGNOR-248650
P54274	O95271	0	ADP-ribosylation	down-regulates activity	0.803	Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA.	SIGNOR-263377
P17612	P13807	1	phosphorylation	down-regulates activity	0.508	The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation	SIGNOR-253009
P26358	Q9BZS1	1	transcriptional regulation	down-regulates quantity by repression	0.488	Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)	SIGNOR-269053
P00533	P25098	1	phosphorylation	up-regulates activity	0.2	Previous studies showed that EGFR activation results in association of GRK2 with the EGFR and subsequent phosphorylation of GRK2 at three tyrosine residues (Tyr 13, -86, and -92), resulting in activation of GRK2.\|We propose that GRK2 activation by EGFR leads to GRK2 phosphorylation of Mst2 at these sites, which, in turn, regulates the Mst2-Nek2A-PP1\u03b3 complex ( xref ).	SIGNOR-279368
Q969T9	P12931	0	phosphorylation	up-regulates activity	0.297	Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα.	SIGNOR-273567
P49585	Q02086	0	transcriptional regulation	down-regulates quantity by repression	0.2	Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells.	SIGNOR-266230
P42229	P17706	0	dephosphorylation	down-regulates activity	0.733	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-133547
P35236	P27361	0	phosphorylation	up-regulates activity	0.693	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.\|	SIGNOR-249475
P28482	Q09472	1	phosphorylation	up-regulates	0.466	Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression.	SIGNOR-156891
P04083	P17252	0	phosphorylation	up-regulates	0.2	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202780
P01019-PRO_0000032458	Q9NY33	0	cleavage	down-regulates quantity by destabilization	0.2	Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. The binding of Ang II to hDPP III may lead to changes in the shape and size of subsite S1, an important catalytic site, so as to promote the decomposition of the substrate.	SIGNOR-268463
P49715	P63279	0	sumoylation	down-regulates activity	0.2	C/EBPalpha interacts directly with the E2 SUMO-conjugating enzyme Ubc9 and can be SUMOylated in vitro using purified recombinant components. Our results indicate that SUMO modification of SC motifs provides a means to rapidly control higher order interactions among transcription factors and suggests that SUMOylation may be a general mechanism to limit transcriptional synergy.	SIGNOR-256334
P12931	Q9Y446	1	phosphorylation	up-regulates activity	0.306	We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS.	SIGNOR-273807
P23582	Q15714	0	transcriptional regulation	up-regulates quantity by expression	0.257	TSC-22 significantly enhanced CNP promoter activity in GH3 cells.	SIGNOR-266226
P16591	P07900	0	phosphorylation	down-regulates activity	0.3	Hsp90 and tyrosine616 are required for Fer tyrosine kinase activity.Taken together, our findings underscore the importance of Hsp90 and the residue, tyrosine616, which resides in the Hsp90 recognition loop, in maintaining Fer tyrosine kinase activity.	SIGNOR-277818
P24941	P07948	0	phosphorylation	down-regulates activity	0.353	We also show that Lyn phosphorylates Tyr15 of Cdk2 and that incubation of Lyn with Cdk2 results in inhibition of Cdk2 activity.	SIGNOR-279204
Q9Y2T1	Q9H2K2	0	ADP-ribosylation	down-regulates quantity by destabilization	0.697	Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.	SIGNOR-263380
Q15334	P41743	0	phosphorylation	up-regulates activity	0.632	This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.	SIGNOR-263179
P11802	Q13761	1	phosphorylation	down-regulates	0.399	Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.	SIGNOR-185120
P54577	Q2TAL8	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269412
Q14457	P53355	0	phosphorylation	up-regulates	0.727	The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.	SIGNOR-183548
P35226	P42771	1	transcriptional regulation	down-regulates quantity by repression	0.455	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,	SIGNOR-253385
P27815	P49137	0	phosphorylation	down-regulates activity	0.347	Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP.	SIGNOR-263078
P00519	P0DP91	1	phosphorylation	up-regulates activity	0.271	These data raise the possibility that tyrosine phosphorylation of CSB by c-Abl promotes redistribution of CSB in the nucleus and enrichment of CSB in the nucleolus in response to oxidative stress	SIGNOR-279317
P17612	Q14847	1	phosphorylation	down-regulates activity	0.306	Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146	SIGNOR-250074

O60260

Q8IWA4

1

ubiquitination

down-regulates quantity

0.2

Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2. Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy.

SIGNOR-272779

P12931

P25098

1

phosphorylation

up-regulates activity

0.2

Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.

SIGNOR-266305

Q9NRR4

P49841

0

phosphorylation

up-regulates activity

0.278

Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.

SIGNOR-264846

P00533

Q9Y6I3

0

relocalization

down-regulates

0.596

Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr.

SIGNOR-182562

P45985

P45984

1

phosphorylation

up-regulates

0.729

Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)

SIGNOR-197998

O94901

P53350

0

phosphorylation

down-regulates activity

0.453

Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions.

SIGNOR-263098

Q9P1A6

Q9UPX8

1

relocalization

up-regulates activity

0.849

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-264590

P03372

P06239

0

phosphorylation

up-regulates

0.382

On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation.

SIGNOR-55853

F7VJQ1

Q00535

0

phosphorylation

up-regulates quantity

0.332

Cdk5 phosphorylated PrP induces the aggregation of non phosphorylated PrP.|Together, these results indicate that S43 is a major Cdk5 phosphorylation site in PrP.

SIGNOR-278920

P01133

O14672

0

cleavage

up-regulates activity

0.566

Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin

SIGNOR-259840

Q13017

Q13882

0

phosphorylation

up-regulates

0.2

Breast tumor kinase phosphorylates p190rhogap to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Brk phosphorylates p190 at the y(1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120rasgap (p120). As a consequence, brk stimulates p190 and attenuates p120 functions, leading to rhoa inactivation and ras activation, respectively.

SIGNOR-181452

P10914

Q00987

0

ubiquitination

down-regulates quantity

0.388

HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation.|IRF-1 ubiquitination by HDM2 is specifically increased during HIV-1 infection in the presence of increasing amounts of Tat and is mediated by the formation of a trimeric complex between Tat, IRF-1, and HDM2, as demonstrated by coimmunoprecipitation analysis (XREF_FIG).

SIGNOR-278590

Q9HD90

Q9HCK8

0

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-268918

P09630

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.26

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260028

Q15139

Q9UQL6

1

phosphorylation

down-regulates activity

0.516

Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes.

SIGNOR-249270

Q96EB6

Q13043

0

phosphorylation

down-regulates activity

0.344

We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.

SIGNOR-279574

Q09472

P52292

1

acetylation

up-regulates

0.357

Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300

SIGNOR-128625

P48058

P05129

0

phosphorylation

up-regulates

0.702

We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.

SIGNOR-97558

P10915

P09238

0

cleavage

down-regulates quantity by destabilization

0.323

Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.

SIGNOR-256332

P05198

P49770

0

guanine nucleotide exchange factor

up-regulates activity

0.802

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269125

Q9P275

P04179

1

deubiquitination

up-regulates quantity by stabilization

0.319

Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life.

SIGNOR-272280

Q969H0

Q9NYY3

0

phosphorylation

down-regulates

0.483

Plk2 regulates centriole duplication through phosphorylation-mediated degradation of fbxw7 (human cdc4).Plk2 phosphorylates fbxw7 on serine 176

SIGNOR-196448

P31749

P49760

1

phosphorylation

up-regulates

0.39

Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva

SIGNOR-167340

P06241

P16885

1

phosphorylation

up-regulates activity

0.575

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-249340

Q04656

P08294

1

null

up-regulates activity

0.696

Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide.

SIGNOR-272267

P27361

P17480

1

phosphorylation

down-regulates

0.579

Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna

SIGNOR-112817

Q14653

P52292

0

relocalization

up-regulates activity

0.2

The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F).

SIGNOR-262514

Q13153

Q9H1Y0

1

phosphorylation

up-regulates quantity by stabilization

0.2

Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. |As PAK1-mediated phosphorylation at residue T101 protects ATG5 from ubiquitination-dependent degradation

SIGNOR-275835

Q15418

P46527

1

phosphorylation

up-regulates activity

0.393

As for other PI3K effectors, RSK1 phosphorylates p27 at T198.|RSK1 overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, and p27 stability.

SIGNOR-279653

O43432

Q96NX5

0

phosphorylation

up-regulates

0.2

Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii).

SIGNOR-197149

Q9UNN4

P68400

0

phosphorylation

up-regulates activity

0.424

ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.

SIGNOR-250873

Q15678

P56945

1

dephosphorylation

down-regulates

0.394

We show that p130 crk-associated substrate (p130cas) is a direct substrate of ptpn14 and that ptpn14 specifically regulates p130cas phosphorylation at tyrosine residue 128 (y128) in colorectal cancer (crc) cells. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation

SIGNOR-197923

Q05397

P16591

0

phosphorylation

up-regulates activity

0.251

The Fer mediated phosphorylation of specific tyrosine residues of FAK was abolished by cotransfection of shRNA against Fer (i.e., shFer), but not by control shRNA, indicating that the phosphorylation of Tyr577, 861, or 925 of FAK in suspended cells was indeed caused by Fer.

SIGNOR-279409

P63000

Q68EM7

0

guanine nucleotide exchange factor

up-regulates activity

0.566

ARHGAP17 is a Rho GTPase-activating protein of Rac1

SIGNOR-272166

Q16620

P22001

1

phosphorylation

down-regulates

0.377

Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein.

SIGNOR-183515

Q9P275

P06748

1

deubiquitination

up-regulates quantity by stabilization

0.39

USP36 deubiquitylated the nucleolar proteins nucleophosmin/B23 and fibrillarin, and stabilized them by counteracting ubiquitylation-mediated proteasomal degradation.

SIGNOR-272290

P62140

P31749

1

dephosphorylation

down-regulates activity

0.386

Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells

SIGNOR-252604

P16410

P06241

0

phosphorylation

up-regulates quantity by stabilization

0.77

CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4.

SIGNOR-251161

P60484

P19784

0

phosphorylation

down-regulates activity

0.704

We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).

SIGNOR-251025

Q9NYV6

P24941

0

phosphorylation

up-regulates

0.508

Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia

SIGNOR-123231

Q2M2I8

Q96CW1

1

phosphorylation

up-regulates

0.79

Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.

SIGNOR-115657

O15217

P0DMV8

0

relocalization

up-regulates activity

0.2

Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation

SIGNOR-264799

Q9NQC7

Q14164

0

phosphorylation

down-regulates activity

0.441

CYLD is phosphorylated by IKK\u03b5 at Ser418.|Together, these observations demonstrate that I\u03baB kinase\u03b5-mediated phosphorylation of CYLD at Ser418 inhibits CYLD deubiquitinase activity.

SIGNOR-278311

P13807

Q96RG2

0

phosphorylation

down-regulates activity

0.508

Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen.

SIGNOR-245866

Q8IYT8

Q9UGI9

1

phosphorylation

down-regulates

0.2

Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.

SIGNOR-173095

Q86WV6

Q9C029

0

ubiquitination

down-regulates quantity by destabilization

0.2

RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation.|Finally, in vitro ubiquitination assays suggested that RNF90 promoted the ubiquitination of MITA directly (Fig 5E and 5F).

SIGNOR-278678

Q92934

P11309

0

phosphorylation

down-regulates activity

0.371

Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.

SIGNOR-250390

P06239

P32119

1

phosphorylation

down-regulates activity

0.2

Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.

SIGNOR-276279

P00533

O14964

1

phosphorylation

up-regulates activity

0.637

We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation

SIGNOR-100246

P46531

Q92831

0

acetylation

up-regulates

0.602

In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia.

SIGNOR-199024

P42773

Q13351

0

transcriptional regulation

up-regulates quantity by expression

0.266

Thus, EKLF is a direct regulator of p18INK4c gene expression, and much of EKLF's role in driving erythroid cell differentiation may occur via p18INK4c.

SIGNOR-266046

Q96PU5

Q9NY46

1

ubiquitination

down-regulates quantity by destabilization

0.283

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

SIGNOR-253464

P40763

Q15262

0

dephosphorylation

down-regulates activity

0.374

In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705).

SIGNOR-277060

P31994

P07948

0

phosphorylation

up-regulates activity

0.43

Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn

SIGNOR-249380

Q9UEY8

P17252

0

phosphorylation

down-regulates quantity by destabilization

0.334

Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin

SIGNOR-249143

P18848

Q9UGM6

1

transcriptional regulation

up-regulates quantity by expression

0.246

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269430

P01106

Q96GD4

0

phosphorylation

up-regulates quantity by stabilization

0.373

AURKB directly phosphorylates MYC at serine 67, counteracting GSK3\u03b2-directed threonine 58 phosphorylation and subsequent FBXW7- mediated proteasomal degradation.

SIGNOR-279439

Q96HS1

Q8IVP5

1

dephosphorylation

up-regulates activity

0.627

Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.

SIGNOR-273654

Q9BW19

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.2

ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.

SIGNOR-277295

Q96PU4

P24864

1

ubiquitination

down-regulates quantity by destabilization

0.332

We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.

SIGNOR-271886

P52630

P23458

0

phosphorylation

up-regulates activity

0.768

STAT2 plays a pivotal role in IFN-a signaling. It is recruited to the activated receptor first and, after phosphorylation by JAK kinases on tyrosine 690, provides a docking site for the SH2 domain of STAT1.

SIGNOR-251344

Q05086

O43166

1

polyubiquitination

down-regulates quantity by destabilization

0.365

the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.

SIGNOR-272608

P49841

P07384

0

cleavage

up-regulates activity

0.297

Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase

SIGNOR-251586

P51608

Q9NWB1

1

transcriptional regulation

down-regulates quantity by repression

0.28

MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.

SIGNOR-264681

O43318

Q13114

0

ubiquitination

up-regulates activity

0.457

Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.|TRAF3 activates TAK1 through ubiquitination.

SIGNOR-278787

Q5GLZ8

Q99835

1

ubiquitination

down-regulates quantity by destabilization

0.2

Our data showed that Herc4 mediated Smo degradation by proteasome and lysosome, but mainly by proteasome.|Using the cell based ubiquitination assay, we found that both Myc-SmoK13R and Myc-SmoK49R exhibited reduced ubiquitination compared with Myc-Smo by Herc4, but Myc-SmoK49R resulted in a more dramatic reduction in Smo ubiquitination (XREF_FIG), suggesting that Smo is ubiquitinated by Herc4 at multiple Lys residues.

SIGNOR-278521

P41162

Q16828

1

transcriptional regulation

down-regulates quantity by repression

0.2

ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation.

SIGNOR-262780

Q13554

Q13224

1

phosphorylation

up-regulates activity

0.606

By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.

SIGNOR-250688

Q96AP0

Q9HC98

0

phosphorylation

up-regulates activity

0.2

NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment|Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase.|

SIGNOR-264424

Q86YD1

Q7Z6Z7

0

ubiquitination

down-regulates quantity

0.2

Our data suggest that HUWE1 can ubiquitinate PTOV1 in vitro and depletion of HUWE1 in cells increases the stability of PTOV1 S36A protein in the nucleus.|Our data suggest that depletion of HUWE1 elevates PTOV1 protein levels, which, in turn, promote the expression of cJun, a pro-growth translational target of PTOV1 (18)\n In our model, we propose that HUWE1 mediates the degradation of PTOV1 in the nucleus.

SIGNOR-278755

Q6J4K2

P17612

0

phosphorylation

up-regulates activity

0.2

However, the PDE2-inhibitory effect is eliminated when the mitochondrial S258A NCLX mutant that mimics a non-PKA phosphorylated state of NCLX is expressed. Altogether, our findings indicate that NCLX is regulated by the mitochondrial PDE2A2 form.|We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. |Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site.

SIGNOR-275727

O00429

Q969V5

0

sumoylation

up-regulates activity

0.534

Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.

SIGNOR-274128

P67775

Q13153

1

dephosphorylation

down-regulates activity

0.357

Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.

SIGNOR-248641

P17612

Q15208

1

phosphorylation

down-regulates activity

0.295

GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively. Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.

SIGNOR-276390

Q9BXL7

P67775

0

dephosphorylation

down-regulates activity

0.309

NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.

SIGNOR-248650

P54274

O95271

0

ADP-ribosylation

down-regulates activity

0.803

Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA.

SIGNOR-263377

P17612

P13807

1

phosphorylation

down-regulates activity

0.508

The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation

SIGNOR-253009

P26358

Q9BZS1

1

transcriptional regulation

down-regulates quantity by repression

0.488

Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)

SIGNOR-269053

P00533

P25098

1

phosphorylation

up-regulates activity

0.2

Previous studies showed that EGFR activation results in association of GRK2 with the EGFR and subsequent phosphorylation of GRK2 at three tyrosine residues (Tyr 13, -86, and -92), resulting in activation of GRK2.|We propose that GRK2 activation by EGFR leads to GRK2 phosphorylation of Mst2 at these sites, which, in turn, regulates the Mst2-Nek2A-PP1\u03b3 complex ( xref ).

SIGNOR-279368

Q969T9

P12931

0

phosphorylation

up-regulates activity

0.297

Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα.

SIGNOR-273567

P49585

Q02086

0

transcriptional regulation

down-regulates quantity by repression

0.2

Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells.

SIGNOR-266230

P42229

P17706

0

dephosphorylation

down-regulates activity

0.733

Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.

SIGNOR-133547

P35236

P27361

0

phosphorylation

up-regulates activity

0.693

First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|

SIGNOR-249475

P28482

Q09472

1

phosphorylation

up-regulates

0.466

Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression.

SIGNOR-156891

P04083

P17252

0

phosphorylation

up-regulates

0.2

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

SIGNOR-202780

P01019-PRO_0000032458

Q9NY33

0

cleavage

down-regulates quantity by destabilization

0.2

Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. The binding of Ang II to hDPP III may lead to changes in the shape and size of subsite S1, an important catalytic site, so as to promote the decomposition of the substrate.

SIGNOR-268463

P49715

P63279

0

sumoylation

down-regulates activity

0.2

C/EBPalpha interacts directly with the E2 SUMO-conjugating enzyme Ubc9 and can be SUMOylated in vitro using purified recombinant components. Our results indicate that SUMO modification of SC motifs provides a means to rapidly control higher order interactions among transcription factors and suggests that SUMOylation may be a general mechanism to limit transcriptional synergy.

SIGNOR-256334

P12931

Q9Y446

1

phosphorylation

up-regulates activity

0.306

We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS.

SIGNOR-273807

P23582

Q15714

0

transcriptional regulation

up-regulates quantity by expression

0.257

TSC-22 significantly enhanced CNP promoter activity in GH3 cells.

SIGNOR-266226

P16591

P07900

0

phosphorylation

down-regulates activity

0.3

Hsp90 and tyrosine616 are required for Fer tyrosine kinase activity.Taken together, our findings underscore the importance of Hsp90 and the residue, tyrosine616, which resides in the Hsp90 recognition loop, in maintaining Fer tyrosine kinase activity.

SIGNOR-277818

P24941

P07948

0

phosphorylation

down-regulates activity

0.353

We also show that Lyn phosphorylates Tyr15 of Cdk2 and that incubation of Lyn with Cdk2 results in inhibition of Cdk2 activity.

SIGNOR-279204

Q9Y2T1

Q9H2K2

0

ADP-ribosylation

down-regulates quantity by destabilization

0.697

Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.

SIGNOR-263380

Q15334

P41743

0

phosphorylation

up-regulates activity

0.632

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

SIGNOR-263179

P11802

Q13761

1

phosphorylation

down-regulates

0.399

Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.

SIGNOR-185120

P54577

Q2TAL8

0

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269412

Q14457

P53355

0

phosphorylation

up-regulates

0.727

The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.

SIGNOR-183548

P35226

P42771

1

transcriptional regulation

down-regulates quantity by repression

0.455

In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,

SIGNOR-253385

P27815

P49137

0

phosphorylation

down-regulates activity

0.347

Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP.

SIGNOR-263078

P00519

P0DP91

1

phosphorylation

up-regulates activity

0.271

These data raise the possibility that tyrosine phosphorylation of CSB by c-Abl promotes redistribution of CSB in the nucleus and enrichment of CSB in the nucleolus in response to oxidative stress

SIGNOR-279317

P17612

Q14847

1

phosphorylation

down-regulates activity

0.306

Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146

SIGNOR-250074