GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P31749	Q15910	1	phosphorylation	down-regulates activity	0.594	Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3	SIGNOR-141043
Q9Y6Q9	Q16659	0	phosphorylation	up-regulates	0.481	Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857)	SIGNOR-196957
O75582	P50549	1	phosphorylation	up-regulates activity	0.463	Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity.	SIGNOR-262987
P40763	P29350	0	dephosphorylation	down-regulates	0.457	Stat3 may also be a substrate of shp1	SIGNOR-178699
Q8IVT5	P15531	0	phosphorylation	down-regulates	0.543	Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site.	SIGNOR-90390
Q9P2J5	Q5S007	0	phosphorylation	down-regulates activity	0.2	In this study, we elucidated that leucyl-tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2-meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers.	SIGNOR-277417
P33981	Q9Y5T5	1	phosphorylation	down-regulates quantity by destabilization	0.37	Usp16 is a TTK phosphorylation substrate.	SIGNOR-277351
P50549	Q13535	0	phosphorylation	up-regulates quantity by stabilization	0.2	Collectively, the results described above indicate that ATR phosphorylates ETV1 and stabilizes it from proteolytic degradation.	SIGNOR-279355
O15516	Q00535	0	phosphorylation	up-regulates	0.328	Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock.	SIGNOR-203227
P31751	O60346	0	dephosphorylation	down-regulates activity	0.621	The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.\|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248328
P29475	Q16566	0	phosphorylation	down-regulates activity	0.357	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-250713
Q9UNE7	P56817	1	ubiquitination	down-regulates quantity	0.378	This result establishes that CHIP negatively regulates BACE1 stability.\|Thus, both deletion mutants of CHIP could not enhance the ubiquitination of BACE1, suggesting that both domains of CHIP were essential for ubiquitination and degradation of BACE1.	SIGNOR-278719
Q16584	O95819	0	phosphorylation	up-regulates activity	0.304	The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling.	SIGNOR-277571
Q92995	Q9H1Y0	1	deubiquitination	up-regulates quantity by stabilization	0.274	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.	SIGNOR-275838
P12036	P49841	0	phosphorylation	down-regulates	0.302	Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment	SIGNOR-90668
P15927	Q8N2W9	0	phosphorylation	up-regulates	0.2	Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation	SIGNOR-162164
P15172	Q92793	0	acetylation	up-regulates	0.616	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81050
P06493	Q9NQS7	1	phosphorylation	up-regulates	0.759	Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase.	SIGNOR-143387
O60841	P55010	0	relocalization	up-regulates activity	0.75	eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.	SIGNOR-269122
P31749	P04150	1	phosphorylation	down-regulates	0.486	Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus	SIGNOR-252543
Q9Y4H4	P49840	0	phosphorylation	down-regulates quantity by destabilization	0.2	Co-immunoprecipitation of endogenous GPSM3 and 14-3-3 proteins from the human monocytic cell line THP-1 suggests basal phosphorylation of GPSM3 at serine 35 as potentially mediated by GSK3alpha. The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins.	SIGNOR-264863
Q01094	P80370	1	transcriptional regulation	up-regulates quantity by expression	0.2	Using luciferase reporter assay, ChIP assay and EMSA, we found that the -211/-194 region of the pref-1 promoter is essential for the binding of E2F1 as well as E2F1-dependent transcriptional activation.	SIGNOR-271684
Q13464	P53667	1	phosphorylation	up-regulates activity	0.617	Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop.	SIGNOR-74569
P22681	Q8WU20	1	ubiquitination	down-regulates	0.576	The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains.	SIGNOR-87166
O15550	P31260	1	transcriptional regulation	up-regulates quantity by expression	0.267	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-260020
Q13315	O96017	1	phosphorylation	up-regulates activity	0.835	Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir	SIGNOR-81403
Q13144	P68400	0	phosphorylation	up-regulates activity	0.386	Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.	SIGNOR-250859
Q9NZH5	P06493	0	phosphorylation	up-regulates activity	0.291	HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis.	SIGNOR-262700
Q9UQL6	Q13555	0	phosphorylation	down-regulates	0.428	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85102
Q8NHZ8	O95835	0	phosphorylation	up-regulates activity	0.466	LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C\|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C\|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly	SIGNOR-275472
P42574	P09874	1	cleavage	down-regulates activity	0.775	Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process	SIGNOR-116178
P05164	P02647	1	oxidation	down-regulates activity	0.406	When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation	SIGNOR-252102
Q14493	Q7Z2G1	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265387
P45983	P14778	0	phosphorylation	up-regulates activity	0.379	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab	SIGNOR-249513
Q7Z2W4	P49841	0	phosphorylation	up-regulates activity	0.2	GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.\|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein.	SIGNOR-278401
P27448	Q15831	0	phosphorylation	up-regulates activity	0.315	Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211.	SIGNOR-104059
P17612	P16220	1	phosphorylation	up-regulates activity	0.581	Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression.	SIGNOR-131307
P05549	P35318	1	transcriptional regulation	up-regulates quantity by expression	0.267	These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.	SIGNOR-254048
P17676	P49675	1	transcriptional regulation	up-regulates quantity by expression	0.365	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254046
P28482	Q14790	1	phosphorylation	down-regulates	0.757	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-203473
P47989	Q00535	0	phosphorylation	up-regulates activity	0.2	Finally, threonine 222 of XOR is the critical target site for CDK5 dependent activation of XOR.\|Once we determined CDK5 was necessary for hypoxia induced hyperactivation of XOR, we tested whether CDK5 was sufficient to phosphorylate XOR and induce increased enzymatic activity in a cell free system.	SIGNOR-280221
P12931	P06733	1	phosphorylation	up-regulates	0.41	The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways	SIGNOR-205092
P43405	Q13191	0	ubiquitination	down-regulates quantity	0.696	In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.\|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.	SIGNOR-278754
Q9GZQ8	Q9Y4K3	0	polyubiquitination	down-regulates quantity by destabilization	0.295	TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes.	SIGNOR-277439
P10636	P49841	0	phosphorylation	down-regulates activity	0.739	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249346
Q96PU4	Q8WW12	1	polyubiquitination	down-regulates quantity by destabilization	0.451	Ubiquitination of PEST containing nuclear protein (PEST) by NIRF (Np95/ICBP90‐like RING finger protein) in the nuclear core of the cell: Ubiquitin‐like domain in the N‐terminus and a RING finger motif in the C‐terminus of NIRF confirm the ubiquitin ligase function of NIRF. PCNP acts as a substrate for NIRF mediated proteasome activity.	SIGNOR-271501
P17252	Q13507	1	phosphorylation	down-regulates	0.348	There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712.	SIGNOR-130269
P43694	P11802	0	phosphorylation	up-regulates activity	0.356	In addition, we have shown that CDK4 can enhance cardiogenic activity of GATA4 (XREF_FIG).\|The physical and functional interactions between GATA4 and Cyclin D2 depend on phosphorylation of Ser 160 of GATA4, which can be mediated in vitro by CDK4.	SIGNOR-279148
P42345	Q13541	1	phosphorylation	down-regulates activity	0.926	Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-167184
P49918	Q16539	0	phosphorylation	up-regulates	0.262	G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest.	SIGNOR-198390
O75460	P17861-2	1	post transcriptional regulation	up-regulates quantity by expression	0.647	Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity.	SIGNOR-260183
P11802	P19484	1	phosphorylation	up-regulates activity	0.2	CDK4 and CDK6 phosphorylate TFEB and TFE3.	SIGNOR-279450
Q12888	P49841	0	phosphorylation	up-regulates activity	0.283	Based on these observations, we hypothesized that the IR induced GSK3beta nuclear translocation may activate 53BP1 via phosphorylation at the S/T-Q motif.\|Importantly, our in vivo and in vitro data clearly indicated that GSK3\u03b2 induced the phosphorylation of 53BP1 at the Ser166 site.	SIGNOR-278226
P41208	Q15154	0	relocalization	up-regulates	0.531	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-94990
P67809	Q8IUQ4	0	ubiquitination	down-regulates quantity by destabilization	0.244	Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain.\|SIAH1 ubiquitinated YBX-1 at its K304 through the RING domain.	SIGNOR-278780
Q9UKX7	P06493	0	phosphorylation	down-regulates	0.421	These results suggest that both ERK and Cdk1 directly phosphorylate Nup50 at Ser221 in intact cells\|Notably, erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.	SIGNOR-188061
O75581	Q8N752	0	phosphorylation	up-regulates	0.254	Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms	SIGNOR-173853
Q8N2M8	P00519	0	phosphorylation	up-regulates activity	0.2	In biochemical assays and in Xenopus growth cones we find that Abl kinase activity enhances the association or co-localization of CLASP2 and F-actin, consistent with previous reports of CLASP binding to actin [Tsvetkov et al., ].\|In vitro, Abl phosphorylates CLASP with a Km of 1.89 \u00b5M, indicating that CLASP is a bona fide substrate.	SIGNOR-280166
Q05513	P78563	1	phosphorylation	up-regulates activity	0.2	Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.	SIGNOR-277391
Q9Y4K3	Q9UDY8	1	ubiquitination	up-regulates	0.755	Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)	SIGNOR-158554
Q14005	P28482	0	phosphorylation	up-regulates	0.265	The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.	SIGNOR-121852
Q99250	Q8NEV1	0	phosphorylation	up-regulates activity	0.2	We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. \| inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275755
P23025	Q13535	0	phosphorylation	up-regulates activity	0.492	ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215.	SIGNOR-258985
Q13043	Q7L9L4	1	phosphorylation	up-regulates	0.851	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-175841
P25963	O14920	0	phosphorylation	down-regulates activity	0.922	Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation	SIGNOR-235400
P46934	Q96GG9	1	monoubiquitination	up-regulates quantity	0.368	Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system.Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1,	SIGNOR-272719
Q13568	Q15306	0	null	down-regulates activity	0.456	IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.	SIGNOR-249560
Q14790	Q16539	0	phosphorylation	down-regulates	0.55	P38-mapk can directly phosphorylate and inhibit the activities of caspase-8	SIGNOR-122103
Q16236	Q05655	0	phosphorylation	up-regulates activity	0.371	Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.	SIGNOR-249161
Q99490	P31749	0	phosphorylation	up-regulates	0.497	In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2.	SIGNOR-183543
P10275	Q15858	1	transcriptional regulation	up-regulates quantity by expression	0.2	In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression.	SIGNOR-253466
P12931	P50570	1	phosphorylation	down-regulates activity	0.557	We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G).	SIGNOR-277539
P54646	Q92819	1	phosphorylation	down-regulates activity	0.2	We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity.	SIGNOR-276299
Q92908	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.308	We identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin.	SIGNOR-277241
P12931	P31943	0	post transcriptional regulation	up-regulates quantity by expression	0.291	HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells.	SIGNOR-261273
P36897	P68104	1	phosphorylation	down-regulates	0.343	Phosphorylation of eEF1A1 at Ser300 by T_R-I results in inhibition of mRNA translation	SIGNOR-167943
P01106	P22626	1	transcriptional regulation	up-regulates quantity by expression	0.356	We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,	SIGNOR-268691
P68400	Q06265	1	phosphorylation	up-regulates	0.2	Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay	SIGNOR-184031
P01135	P78536	0	cleavage	up-regulates activity	0.489	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259841
Q9BWT7	A7MCY6	0	relocalization	up-regulates activity	0.2	TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272470
P17252	Q15172	1	phosphorylation	down-regulates activity	0.341	In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα.	SIGNOR-276603
P17612	Q86UR1	1	phosphorylation	down-regulates	0.324	We identified ser-282 as target of mapk and ser-172 as target of pkc and pka in vitro and in a transfected human embryonic kidney 293 (hek293) cell model using site directed mutagenesis and phosphopeptide mapping analysis. In hek293 cells, phosphorylation of these sites occurred at a basal level and down-regulated constitutive nox1 activity. I	SIGNOR-163663
Q13950	Q9UQL6	0	deacetylation	down-regulates	0.458	Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation	SIGNOR-145983
P45983	Q16828	0	dephosphorylation	down-regulates activity	0.632	Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.\|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells.	SIGNOR-277150
Q9HD90	Q12857	0	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268891
Q92823	P16157	1	relocalization	up-regulates quantity	0.544	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266721
Q96LC7	P52333	0	phosphorylation	up-regulates	0.2	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112479
P00352	Q00535	0	phosphorylation	up-regulates quantity	0.2	Cdk5 Phosphorylates ALDH1A1 at S75 and S274.\|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites.	SIGNOR-279399
P15173	P23409	1	transcriptional regulation	up-regulates quantity by expression	0.433	[...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site.	SIGNOR-255642
P17612	P49841	1	phosphorylation	down-regulates activity	0.557	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188577
Q99759	Q13163	1	phosphorylation	up-regulates	0.72	Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.	SIGNOR-104637
P49840	Q9Y5Q3	1	phosphorylation	down-regulates	0.2	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159432
Q96PU5	P35240	1	ubiquitination	up-regulates activity	0.261	Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.	SIGNOR-263662
Q9P2K8	P56192	1	phosphorylation	down-regulates	0.2	Here we demonstrate that aimp3 is released from mrs by uv irradiation-induced stress. Dissociation was induced by phosphorylation of mrs at ser662 by general control nonrepressed-2 (gcn2) following uv irradiation. Substitution of ser662 to asp (s662d) induced a conformational change in mrs and significantly reduced its interaction with aimp3. This mutant possessed significantly reduced mrs catalytic activity because of loss of trna(met) binding, resulting in down-regulation of global translation.	SIGNOR-177648
Q86YJ5	Q9BV40	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271531
O60825	Q13131	0	phosphorylation	up-regulates activity	0.464	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-84061
P40763	O14522	0	dephosphorylation	down-regulates activity	0.516	Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T\|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.	SIGNOR-263981
Q05655	P23470	0	dephosphorylation	up-regulates activity	0.2	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254716
Q09472	Q9UPG8	1	acetylation	up-regulates	0.2	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140947
P42345	Q9Y2J4	1	phosphorylation	down-regulates activity	0.2	AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets.	SIGNOR-272086

P31749

Q15910

1

phosphorylation

down-regulates activity

0.594

Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3

SIGNOR-141043

Q9Y6Q9

Q16659

0

phosphorylation

up-regulates

0.481

Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857)

SIGNOR-196957

O75582

P50549

1

phosphorylation

up-regulates activity

0.463

Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity.

SIGNOR-262987

P40763

P29350

0

dephosphorylation

down-regulates

0.457

Stat3 may also be a substrate of shp1

SIGNOR-178699

Q8IVT5

P15531

0

phosphorylation

down-regulates

0.543

Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site.

SIGNOR-90390

Q9P2J5

Q5S007

0

phosphorylation

down-regulates activity

0.2

In this study, we elucidated that leucyl-tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2-meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers.

SIGNOR-277417

P33981

Q9Y5T5

1

phosphorylation

down-regulates quantity by destabilization

0.37

Usp16 is a TTK phosphorylation substrate.

SIGNOR-277351

P50549

Q13535

0

phosphorylation

up-regulates quantity by stabilization

0.2

Collectively, the results described above indicate that ATR phosphorylates ETV1 and stabilizes it from proteolytic degradation.

SIGNOR-279355

O15516

Q00535

0

phosphorylation

up-regulates

0.328

Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock.

SIGNOR-203227

P31751

O60346

0

dephosphorylation

down-regulates activity

0.621

The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.

SIGNOR-248328

P29475

Q16566

0

phosphorylation

down-regulates activity

0.357

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-250713

Q9UNE7

P56817

1

ubiquitination

down-regulates quantity

0.378

This result establishes that CHIP negatively regulates BACE1 stability.|Thus, both deletion mutants of CHIP could not enhance the ubiquitination of BACE1, suggesting that both domains of CHIP were essential for ubiquitination and degradation of BACE1.

SIGNOR-278719

Q16584

O95819

0

phosphorylation

up-regulates activity

0.304

The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling.

SIGNOR-277571

Q92995

Q9H1Y0

1

deubiquitination

up-regulates quantity by stabilization

0.274

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.

SIGNOR-275838

P12036

P49841

0

phosphorylation

down-regulates

0.302

Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment

SIGNOR-90668

P15927

Q8N2W9

0

phosphorylation

up-regulates

0.2

Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation

SIGNOR-162164

P15172

Q92793

0

acetylation

up-regulates

0.616

Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.

SIGNOR-81050

P06493

Q9NQS7

1

phosphorylation

up-regulates

0.759

Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase.

SIGNOR-143387

O60841

P55010

0

relocalization

up-regulates activity

0.75

eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.

SIGNOR-269122

P31749

P04150

1

phosphorylation

down-regulates

0.486

Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus

SIGNOR-252543

Q9Y4H4

P49840

0

phosphorylation

down-regulates quantity by destabilization

0.2

Co-immunoprecipitation of endogenous GPSM3 and 14-3-3 proteins from the human monocytic cell line THP-1 suggests basal phosphorylation of GPSM3 at serine 35 as potentially mediated by GSK3alpha. The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins.

SIGNOR-264863

Q01094

P80370

1

transcriptional regulation

up-regulates quantity by expression

0.2

Using luciferase reporter assay, ChIP assay and EMSA, we found that the -211/-194 region of the pref-1 promoter is essential for the binding of E2F1 as well as E2F1-dependent transcriptional activation.

SIGNOR-271684

Q13464

P53667

1

phosphorylation

up-regulates activity

0.617

Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop.

SIGNOR-74569

P22681

Q8WU20

1

ubiquitination

down-regulates

0.576

The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains.

SIGNOR-87166

O15550

P31260

1

transcriptional regulation

up-regulates quantity by expression

0.267

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-260020

Q13315

O96017

1

phosphorylation

up-regulates activity

0.835

Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir

SIGNOR-81403

Q13144

P68400

0

phosphorylation

up-regulates activity

0.386

Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.

SIGNOR-250859

Q9NZH5

P06493

0

phosphorylation

up-regulates activity

0.291

HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis.

SIGNOR-262700

Q9UQL6

Q13555

0

phosphorylation

down-regulates

0.428

Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.

SIGNOR-85102

Q8NHZ8

O95835

0

phosphorylation

up-regulates activity

0.466

LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly

SIGNOR-275472

P42574

P09874

1

cleavage

down-regulates activity

0.775

Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process

SIGNOR-116178

P05164

P02647

1

oxidation

down-regulates activity

0.406

When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation

SIGNOR-252102

Q14493

Q7Z2G1

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265387

P45983

P14778

0

phosphorylation

up-regulates activity

0.379

Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab

SIGNOR-249513

Q7Z2W4

P49841

0

phosphorylation

up-regulates activity

0.2

GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein.

SIGNOR-278401

P27448

Q15831

0

phosphorylation

up-regulates activity

0.315

Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211.

SIGNOR-104059

P17612

P16220

1

phosphorylation

up-regulates activity

0.581

Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression.

SIGNOR-131307

P05549

P35318

1

transcriptional regulation

up-regulates quantity by expression

0.267

These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.

SIGNOR-254048

P17676

P49675

1

transcriptional regulation

up-regulates quantity by expression

0.365

Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.

SIGNOR-254046

P28482

Q14790

1

phosphorylation

down-regulates

0.757

We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity

SIGNOR-203473

P47989

Q00535

0

phosphorylation

up-regulates activity

0.2

Finally, threonine 222 of XOR is the critical target site for CDK5 dependent activation of XOR.|Once we determined CDK5 was necessary for hypoxia induced hyperactivation of XOR, we tested whether CDK5 was sufficient to phosphorylate XOR and induce increased enzymatic activity in a cell free system.

SIGNOR-280221

P12931

P06733

1

phosphorylation

up-regulates

0.41

The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways

SIGNOR-205092

P43405

Q13191

0

ubiquitination

down-regulates quantity

0.696

In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.

SIGNOR-278754

Q9GZQ8

Q9Y4K3

0

polyubiquitination

down-regulates quantity by destabilization

0.295

TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes.

SIGNOR-277439

P10636

P49841

0

phosphorylation

down-regulates activity

0.739

We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.

SIGNOR-249346

Q96PU4

Q8WW12

1

polyubiquitination

down-regulates quantity by destabilization

0.451

Ubiquitination of PEST containing nuclear protein (PEST) by NIRF (Np95/ICBP90‐like RING finger protein) in the nuclear core of the cell: Ubiquitin‐like domain in the N‐terminus and a RING finger motif in the C‐terminus of NIRF confirm the ubiquitin ligase function of NIRF. PCNP acts as a substrate for NIRF mediated proteasome activity.

SIGNOR-271501

P17252

Q13507

1

phosphorylation

down-regulates

0.348

There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712.

SIGNOR-130269

P43694

P11802

0

phosphorylation

up-regulates activity

0.356

In addition, we have shown that CDK4 can enhance cardiogenic activity of GATA4 (XREF_FIG).|The physical and functional interactions between GATA4 and Cyclin D2 depend on phosphorylation of Ser 160 of GATA4, which can be mediated in vitro by CDK4.

SIGNOR-279148

P42345

Q13541

1

phosphorylation

down-regulates activity

0.926

Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation

SIGNOR-167184

P49918

Q16539

0

phosphorylation

up-regulates

0.262

G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest.

SIGNOR-198390

O75460

P17861-2

1

post transcriptional regulation

up-regulates quantity by expression

0.647

Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity.

SIGNOR-260183

P11802

P19484

1

phosphorylation

up-regulates activity

0.2

CDK4 and CDK6 phosphorylate TFEB and TFE3.

SIGNOR-279450

Q12888

P49841

0

phosphorylation

up-regulates activity

0.283

Based on these observations, we hypothesized that the IR induced GSK3beta nuclear translocation may activate 53BP1 via phosphorylation at the S/T-Q motif.|Importantly, our in vivo and in vitro data clearly indicated that GSK3\u03b2 induced the phosphorylation of 53BP1 at the Ser166 site.

SIGNOR-278226

P41208

Q15154

0

relocalization

up-regulates

0.531

Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome

SIGNOR-94990

P67809

Q8IUQ4

0

ubiquitination

down-regulates quantity by destabilization

0.244

Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain.|SIAH1 ubiquitinated YBX-1 at its K304 through the RING domain.

SIGNOR-278780

Q9UKX7

P06493

0

phosphorylation

down-regulates

0.421

These results suggest that both ERK and Cdk1 directly phosphorylate Nup50 at Ser221 in intact cells|Notably, erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.

SIGNOR-188061

O75581

Q8N752

0

phosphorylation

up-regulates

0.254

Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms

SIGNOR-173853

Q8N2M8

P00519

0

phosphorylation

up-regulates activity

0.2

In biochemical assays and in Xenopus growth cones we find that Abl kinase activity enhances the association or co-localization of CLASP2 and F-actin, consistent with previous reports of CLASP binding to actin [Tsvetkov et al., ].|In vitro, Abl phosphorylates CLASP with a Km of 1.89 \u00b5M, indicating that CLASP is a bona fide substrate.

SIGNOR-280166

Q05513

P78563

1

phosphorylation

up-regulates activity

0.2

Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.

SIGNOR-277391

Q9Y4K3

Q9UDY8

1

ubiquitination

up-regulates

0.755

Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)

SIGNOR-158554

Q14005

P28482

0

phosphorylation

up-regulates

0.265

The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.

SIGNOR-121852

Q99250

Q8NEV1

0

phosphorylation

up-regulates activity

0.2

We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.

SIGNOR-275755

P23025

Q13535

0

phosphorylation

up-regulates activity

0.492

ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215.

SIGNOR-258985

Q13043

Q7L9L4

1

phosphorylation

up-regulates

0.851

Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.

SIGNOR-175841

P25963

O14920

0

phosphorylation

down-regulates activity

0.922

Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation

SIGNOR-235400

P46934

Q96GG9

1

monoubiquitination

up-regulates quantity

0.368

Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system.Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1,

SIGNOR-272719

Q13568

Q15306

0

null

down-regulates activity

0.456

IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.

SIGNOR-249560

Q14790

Q16539

0

phosphorylation

down-regulates

0.55

P38-mapk can directly phosphorylate and inhibit the activities of caspase-8

SIGNOR-122103

Q16236

Q05655

0

phosphorylation

up-regulates activity

0.371

Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.

SIGNOR-249161

Q99490

P31749

0

phosphorylation

up-regulates

0.497

In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2.

SIGNOR-183543

P10275

Q15858

1

transcriptional regulation

up-regulates quantity by expression

0.2

In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression.

SIGNOR-253466

P12931

P50570

1

phosphorylation

down-regulates activity

0.557

We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G).

SIGNOR-277539

P54646

Q92819

1

phosphorylation

down-regulates activity

0.2

We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity.

SIGNOR-276299

Q92908

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.308

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

SIGNOR-277241

P12931

P31943

0

post transcriptional regulation

up-regulates quantity by expression

0.291

HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells.

SIGNOR-261273

P36897

P68104

1

phosphorylation

down-regulates

0.343

Phosphorylation of eEF1A1 at Ser300 by T_R-I results in inhibition of mRNA translation

SIGNOR-167943

P01106

P22626

1

transcriptional regulation

up-regulates quantity by expression

0.356

We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,

SIGNOR-268691

P68400

Q06265

1

phosphorylation

up-regulates

0.2

Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay

SIGNOR-184031

P01135

P78536

0

cleavage

up-regulates activity

0.489

ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF

SIGNOR-259841

Q9BWT7

A7MCY6

0

relocalization

up-regulates activity

0.2

TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation

SIGNOR-272470

P17252

Q15172

1

phosphorylation

down-regulates activity

0.341

In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα.

SIGNOR-276603

P17612

Q86UR1

1

phosphorylation

down-regulates

0.324

We identified ser-282 as target of mapk and ser-172 as target of pkc and pka in vitro and in a transfected human embryonic kidney 293 (hek293) cell model using site directed mutagenesis and phosphopeptide mapping analysis. In hek293 cells, phosphorylation of these sites occurred at a basal level and down-regulated constitutive nox1 activity. I

SIGNOR-163663

Q13950

Q9UQL6

0

deacetylation

down-regulates

0.458

Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation

SIGNOR-145983

P45983

Q16828

0

dephosphorylation

down-regulates activity

0.632

Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells.

SIGNOR-277150

Q9HD90

Q12857

0

transcriptional regulation

up-regulates quantity

0.2

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

SIGNOR-268891

Q92823

P16157

1

relocalization

up-regulates quantity

0.544

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

SIGNOR-266721

Q96LC7

P52333

0

phosphorylation

up-regulates

0.2

These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling

SIGNOR-112479

P00352

Q00535

0

phosphorylation

up-regulates quantity

0.2

Cdk5 Phosphorylates ALDH1A1 at S75 and S274.|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites.

SIGNOR-279399

P15173

P23409

1

transcriptional regulation

up-regulates quantity by expression

0.433

[...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site.

SIGNOR-255642

P17612

P49841

1

phosphorylation

down-regulates activity

0.557

Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).

SIGNOR-188577

Q99759

Q13163

1

phosphorylation

up-regulates

0.72

Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.

SIGNOR-104637

P49840

Q9Y5Q3

1

phosphorylation

down-regulates

0.2

We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.

SIGNOR-159432

Q96PU5

P35240

1

ubiquitination

up-regulates activity

0.261

Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.

SIGNOR-263662

Q9P2K8

P56192

1

phosphorylation

down-regulates

0.2

Here we demonstrate that aimp3 is released from mrs by uv irradiation-induced stress. Dissociation was induced by phosphorylation of mrs at ser662 by general control nonrepressed-2 (gcn2) following uv irradiation. Substitution of ser662 to asp (s662d) induced a conformational change in mrs and significantly reduced its interaction with aimp3. This mutant possessed significantly reduced mrs catalytic activity because of loss of trna(met) binding, resulting in down-regulation of global translation.

SIGNOR-177648

Q86YJ5

Q9BV40

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271531

O60825

Q13131

0

phosphorylation

up-regulates activity

0.464

Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.

SIGNOR-84061

P40763

O14522

0

dephosphorylation

down-regulates activity

0.516

Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.

SIGNOR-263981

Q05655

P23470

0

dephosphorylation

up-regulates activity

0.2

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254716

Q09472

Q9UPG8

1

acetylation

up-regulates

0.2

Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.

SIGNOR-140947

P42345

Q9Y2J4

1

phosphorylation

down-regulates activity

0.2

AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets.

SIGNOR-272086