GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q13131	P04049	1	phosphorylation	down-regulates	0.342	Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259. The catalytic subunit of PKA also phosphorylated Ser621 in vitro, while its overexpression in intact cells resulted in increased phosphorylation of Ser621 and decreased activity of Raf-1. These results suggest that phosphorylation of Ser621 inactivates Raf-1, but do not prove that PKA is responsible for this in vivo.	SIGNOR-47148
Q9UBK2	P49760	0	phosphorylation	down-regulates activity	0.2	Clk2 could also repress PGC-1alpha activation of Foxo1 on the IRS response element , as well as repress the Pepck promoter .\|Clk2 phosphorylates and represses PGC-1\u03b1.	SIGNOR-278228
Q92585	O60563	1	relocalization	up-regulates	0.2	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130712
P06241	P35613-2	1	phosphorylation	up-regulates activity	0.269	Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment.	SIGNOR-273999
O43164	P17612	0	phosphorylation	up-regulates activity	0.2	In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h).	SIGNOR-276316
Q71F56	Q969H0	0	ubiquitination	down-regulates quantity by destabilization	0.359	The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.	SIGNOR-266688
Q00535	O15516	1	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
P45983	Q96EB6	1	phosphorylation	up-regulates	0.601	Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53.	SIGNOR-162314
P05771	Q13131	1	phosphorylation	down-regulates activity	0.2	Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle.	SIGNOR-276460
P24941	P20248	1	phosphorylation	up-regulates	0.977	Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154	SIGNOR-74466
P36897	O75604	0	deubiquitination	up-regulates activity	0.2	Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1.	SIGNOR-273605
Q9NYV6	P45984	0	phosphorylation	down-regulates	0.472	Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation.	SIGNOR-134878
Q96PU5	P17612	0	phosphorylation	down-regulates	0.2	Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246).	SIGNOR-128429
Q14012	P49757	1	phosphorylation	down-regulates	0.334	Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2.	SIGNOR-149993
Q13535	Q02952	1	phosphorylation	up-regulates activity	0.2	The expression of either ATR-KD or the addition of the ATR kinase inhibitor VE-821 to ATR-WT expressing cells caused AKAP12 to be retained within the cytoplasm.\|With UV damage, ATR phosphorylates AKAP12 at S732 which stimulates nuclear translocation of an AKAP12\u2013ATR-pS435 complex that results in enhanced 5\u2032 strand incision of NER.	SIGNOR-278292
Q15052	Q04759	0	phosphorylation	up-regulates activity	0.2	Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation.\|More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway.	SIGNOR-272168
Q13905	P08631	0	phosphorylation	up-regulates	0.498	We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4.	SIGNOR-203613
Q96R06	Q9UNH5	0	dephosphorylation	down-regulates activity	0.2	We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment.	SIGNOR-277066
P49336	P36956	1	phosphorylation	up-regulates activity	0.474	Biochemical analyses reveal that SREBP-1c can be directly phosphorylated by CDK8 at the conserved Threonine-402 residue (T402) in vitro and in cultured mammalian cells ( xref ).\|Therefore, the mechanism of CDK8 regulating SREBP functions is primarily through the phosphorylation initiated control of nuclear SREBP-1 protein stability.	SIGNOR-279688
P49768	Q05513	0	phosphorylation	up-regulates activity	0.337	A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.	SIGNOR-249239
P31749	P98170	1	phosphorylation	up-regulates quantity by stabilization	0.618	Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.	SIGNOR-119488
Q13114	Q96PU5	0	ubiquitination	up-regulates activity	0.27	Nedd4l promotes TRAF3 to interact with cIAP1/2 and HECTD3.\|Ubiquitination of TRAF3 by Nedd4l promotes interaction of TRAF3 with proteins such as cIAP1/2, HECTD3, and TBK1.	SIGNOR-278587
O43474	Q7Z6Z7	0	ubiquitination	down-regulates quantity by destabilization	0.34	K48 linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression.\|Instead, we identified the transcription factor KLF4 as a novel Mule substrate that is ubiquitinated by this E3 ligase and thus undergoes proteasomal degradation in T cells.\|Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase.	SIGNOR-278749
P04150	P28482	0	phosphorylation	down-regulates activity	0.623	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.\|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-249428
Q9UBS5	Q13554	0	phosphorylation	down-regulates quantity by destabilization	0.2	ERK1/2 and CaMKIIβ mediated phosphorylation of GABAB1 at serine 867 (S867) and threonine 872 (T872). We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1.	SIGNOR-277851
Q92630	O75449	1	phosphorylation	down-regulates quantity by destabilization	0.509	DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d).	SIGNOR-262847
P35222	O75582	0	phosphorylation	up-regulates activity	0.2	Co-transfection of MSK1 increased beta-catenin transcriptional activity in a dose dependent manner (XREF_FIG).\|Our in vitro kinase assay showed that MSK1 can directly phosphorylate beta-catenin at Ser 552.	SIGNOR-278247
P08922	P18031	0	dephosphorylation	down-regulates	0.374	In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products.	SIGNOR-154199
P27361	Q96Q27	1	phosphorylation	up-regulates activity	0.265	Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. \|Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation.	SIGNOR-272241
Q9HA82	P68400	0	phosphorylation	up-regulates activity	0.2	Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.	SIGNOR-273984
Q13153	O95863	1	phosphorylation	up-regulates	0.4	Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions.	SIGNOR-135605
P13569	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.471	Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination.	SIGNOR-272584
O95644	P17612	0	phosphorylation	down-regulates	0.385	Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)	SIGNOR-93531
Q13485	P28482	0	phosphorylation	up-regulates	0.511	Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276.	SIGNOR-101660
P04040	P00519	0	phosphorylation	up-regulates activity	0.403	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-101302
Q96KB5	P12931	0	phosphorylation	up-regulates quantity by stabilization	0.395	Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon	SIGNOR-277217
Q9UNH5	P04637	1	dephosphorylation	down-regulates activity	0.401	The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53\|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)\|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification	SIGNOR-248828
O95271	P54274	1	ADP-ribosylation	down-regulates activity	0.803	Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA.	SIGNOR-263377
P40763	P16591	0	phosphorylation	up-regulates activity	0.402	Replacing the unique 43-amino acid-long N-terminal tail of p51 (ferT) with a parallel segment from the N-terminal tail of p94 (fer) did not change the subcellular localization of p51 (ferT) but enabled it to activate Stat3.\|When combined with immunoprecipitation analysis, this assay showed that p94 (fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2.	SIGNOR-279713
P51449	O00327	1	transcriptional regulation	up-regulates quantity by expression	0.502	As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression.	SIGNOR-268004
P06239	Q99704	1	phosphorylation	up-regulates activity	0.6	Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates.	SIGNOR-251373
Q16665	Q92544	1	transcriptional regulation	down-regulates quantity by repression	0.2	Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion.	SIGNOR-266705
P06493	O14994	1	phosphorylation	up-regulates	0.2	A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action.	SIGNOR-121398
P25098	Q96A54	1	phosphorylation	down-regulates activity	0.2	AdipoR1 is Directly Phosphorylated by GRK2.\|In summary, our study demonstrates for the first time that cardiometabolic-regulatory, anti-inflammatory, and cardioprotective functions of APN are significantly impaired by GRK2 mediated AdipoR1 phosphorylative desensitization during a critical period of post-MI HF development.	SIGNOR-279463
Q00536	P46459	1	phosphorylation	down-regulates activity	0.439	Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self association of NSF.\|We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569.	SIGNOR-279511
Q969K3	Q9UBK2	1	ubiquitination	down-regulates quantity by destabilization	0.319	Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.	SIGNOR-277912
O14640	Q9Y283	0	ubiquitination	down-regulates	0.641	Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation	SIGNOR-135766
Q8WYH8	P24941	0	phosphorylation	up-regulates quantity	0.401	We report that ING5 is phosphorylated in a cell cycle dependent manner by CDK2 at T152 (Figs 1 and 3).	SIGNOR-279447
P31751	P98170	1	phosphorylation	up-regulates	0.42	Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt.	SIGNOR-119492
Q9UNE7	Q8IXT1	1	ubiquitination	down-regulates quantity by destabilization	0.322	HSP70 recruits DDIAS to the CHIP E3 ligase, whereas CHIP promotes the ubiquitination of DDIAS.\|However, the findings clearly demonstrated that HSP70 was solely involved in CHIP mediated proteasomal degradation of DDIAS.	SIGNOR-278784
P62714	P11233	1	dephosphorylation	down-regulates	0.289	Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function	SIGNOR-155349
P07948	O60711	1	phosphorylation	up-regulates activity	0.375	Of a total of 11 tyrosine sites in LPXN, we mutated Tyr(22), Tyr(72), Tyr(198), and Tyr(257) to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr(72) and that this tyrosine site is proximal to the LD3 domain. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr(72) is critical for the biological function of LPXN.	SIGNOR-262892
O14950	Q13153	0	phosphorylation	up-regulates activity	0.484	It has been shown that PAK1 phosphorylates and activates MLC2, leading to cell motility [ xref ].	SIGNOR-280053
P52732	Q9HC98	0	phosphorylation	up-regulates activity	0.444	Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.	SIGNOR-273886
P17252	Q8NF50	1	phosphorylation	down-regulates activity	0.2	In response to chemokine stimulation, PKC\u03b1 phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration.\|Taken our data together, we suggest that PKC\u03b1 phosphorylates DOCK8 at the Ser2077/2082/2087 sites to promote T cell migration.	SIGNOR-279384
Q9Y2U5	P49023	1	phosphorylation	down-regulates quantity	0.362	As MEKK2 kinase activity is required for this function, our findings support a model of paxillin modification wherein MEKK2 directly phosphorylates and targets paxillin for ubiquitylation.	SIGNOR-278955
P14598	P27361	0	phosphorylation	up-regulates	0.42	Upon activation, several serine residues on the cytosolic oxidase subunit p47phox become phosphorylated. Mitogen-activated protein kinase phophorylated only the peptide containing ser345/348.	SIGNOR-40821
Q8TCJ2	Q9NZQ7	1	glycosylation	up-regulates quantity by stabilization	0.2	Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization.	SIGNOR-274976
O75385	Q9Y4P1	1	phosphorylation	down-regulates activity	0.614	Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316.\|Thus ULK1 is able to inhibit LC3 processing by a direct effect on ATG4B, possibly by phosphorylation of a serine residue of ATG4B.Fig. 1ULK1 inhibits ATG4B-mediated LC3 cleavage. a Average ATG4B activity in Actin-LC3-DelN Luciferase HEK293T obtained by measuring the secreted luciferase activity 48 h after transfection with the indicated constructs (n = 3, average \u00b1 s.d.) and representative immunoblot from one experiment showing expression of the different constructs. b GST-LC3 assay to measure in vitro activity of recombinant ATG4B after incubation with active recombinant ULK1.	SIGNOR-279434
P49841	O43602	1	phosphorylation	up-regulates activity	0.271	Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact.	SIGNOR-170755
O15198	Q13485	1	phosphorylation	up-regulates	0.685	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168740
P06213	Q12923	0	dephosphorylation	down-regulates	0.26	We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.	SIGNOR-132555
P31751	Q6ZVD8	0	dephosphorylation	down-regulates activity	0.604	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-248729
Q06187	P19174	1	phosphorylation	up-regulates activity	0.581	Then, BTK and ITK are activated by Src kinases and proceed to phosphorylate the lipase PLCgamma2 / PLCgamma1, which cleaves PIP2 in the plasma membrane and generates the secondary messengers IP3 and DAG.	SIGNOR-279444
O00712	A8MYZ6	1	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268881
Q14164	Q04206	1	phosphorylation	up-regulates	0.439	Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.	SIGNOR-129943
P01019-PRO_0000032458	P12821	0	cleavage	up-regulates quantity	0.2	Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I	SIGNOR-260236
P15172	P17661	1	transcriptional regulation	down-regulates quantity by repression	0.24	MyoD and HDAC2 repress myogenic late genes at early times of differentiation.A time course of Ckm, Des and Acta1 gene expression demonstrated that these genes were prematurely expressed when differentiation was driven by myogenin and Mef2D1b (Figure _(Figure6A).6A). Since MyoD is not expressed under these conditions, it cannot bind to these genes; ChIP assays demonstrated that HDAC2 also was not present on the Ckm, Des and Acta1 regulatory sequences under these conditions (Figure _(Figure6B).6B). Therefore the presence of MyoD and HDAC2 prior to gene expression functions to repress late gene expression at early times of differentiation.	SIGNOR-241762
Q15154	P51955	1	relocalization	up-regulates	0.425	Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1	SIGNOR-133337
P06493	Q8TD19	1	phosphorylation	up-regulates activity	0.482	We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1.	SIGNOR-273889
P23634-6	Q05397	0	phosphorylation	up-regulates activity	0.2	Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif.	SIGNOR-263194
Q16584	Q92918	0	phosphorylation	up-regulates	0.574	Hpk1 also phosphorylated mlk-3 activation loop in vitro, and ser281 was found to be the major phosphorylation site, indicating that hpk1 also activates mlk-3 via phosphorylation of the kinase activation loop.	SIGNOR-83415
O75925	Q5U5R9	0	polyubiquitination	down-regulates quantity by destabilization	0.389	We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model.	SIGNOR-272421
Q14493	Q16695	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-265417
P54132	Q86YT6	0	ubiquitination	down-regulates quantity by destabilization	0.281	BLM is Ubiquitinated by E3 Ligase MIB1.\|Moreover, MIB1 mediated BLM degradation in G1 phase appears to be important for DNA double-strand break repair.	SIGNOR-278548
Q07812	Q9UPU5	0	deubiquitination	up-regulates quantity by stabilization	0.2	In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. \|Knockdown of USP24 decreases Bax and p300 levels	SIGNOR-275606
Q5JVS0	Q05655	0	phosphorylation	down-regulates activity	0.29	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249254
Q12778	Q9HCE7	1	transcriptional regulation	up-regulates quantity	0.248	FoxO factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1), leading to the ubiquitylation of myosin and other muscle proteins (see below), and their degradation via the proteasome	SIGNOR-256268
O15294	Q01813	1	glycosylation	down-regulates activity	0.257	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity\|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.	SIGNOR-267583
O75581	P28482	0	phosphorylation	up-regulates	0.301	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-169001
Q9UN37	Q9Y3E7	1	cleavage	up-regulates activity	0.625	Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.	SIGNOR-260847
P19784	Q92769	1	phosphorylation	up-regulates activity	0.39	HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. \| Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2.	SIGNOR-251001
Q8NB16	Q9Y572	0	phosphorylation	up-regulates activity	0.753	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266427
P11831	P17612	0	phosphorylation	up-regulates	0.256	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. \| Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.	SIGNOR-188177
P06730	Q9UDX5	1	translation regulation	up-regulates activity	0.2	In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1	SIGNOR-275429
Q9GZV5	P06493	0	phosphorylation	down-regulates activity	0.258	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276518
Q9H3D4	P24941	0	phosphorylation	down-regulates	0.246	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180759
Q9UHD2	Q04206	1	phosphorylation	up-regulates	0.614	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129951
P05412	P00519	0	phosphorylation	up-regulates activity	0.526	Active nuclear Abl efficiently phosphorylate c-Jun. After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl.	SIGNOR-251428
P49023	Q99942	0	ubiquitination	down-regulates quantity	0.407	Here we demonstrate that the human homologue of RNF5 associates with the amino-terminal domain of paxillin, resulting in its ubiquitination. RNF5 requires intact RING and C-terminal domains to mediate paxillin ubiquitination. Concomitantly, RNF5 expression results in inhibition of cell motility. Via targeting of paxillin ubiquitination, which alters its localization, RNF5 emerges as a novel regulator of cell motility.	SIGNOR-271479
P28482	P04150	1	phosphorylation	down-regulates activity	0.623	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.\|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-249428
P42858	Q00535	0	phosphorylation	up-regulates	0.447	Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.	SIGNOR-156840
P00533	P48050	1	phosphorylation	up-regulates activity	0.2	These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K(IR) 2.3 channel via phosphorylation of the Y234 residue of the WT protein.	SIGNOR-276322
Q9BZS1	P84022	0	null	up-regulates	0.523	The TCR, IL-2R, and TbetaR must all be stimulated to induce Foxp3 + Tregs. Failure to engage any one of these receptors prevents the generation of Foxp3 + Tregs	SIGNOR-254363
P05412	P04150	0	transcriptional regulation	down-regulates quantity by repression	0.743	We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins	SIGNOR-251679
Q8WU20	P22455	0	phosphorylation	up-regulates activity	0.685	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-242661
P13640	Q16236	0	transcriptional regulation	up-regulates quantity by expression	0.286	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. The expression of MT1G during ferroptosis is regulated by the NFE2L2 signaling pathway. In the context of cancer, particularly HCC, the upregulation of MT1G has been linked to resistance against sorafenib, a kinase inhibitor commonly used in cancer therapy	SIGNOR-279866
O43781	Q9Y6Q9	1	phosphorylation	down-regulates activity	0.2	Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity.	SIGNOR-275451
P50616	P27361	0	phosphorylation	down-regulates	0.352	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk	SIGNOR-88728
Q9Y463	P20823	1	phosphorylation	up-regulates	0.502	Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk	SIGNOR-86728

Q13131

P04049

1

phosphorylation

down-regulates

0.342

Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259. The catalytic subunit of PKA also phosphorylated Ser621 in vitro, while its overexpression in intact cells resulted in increased phosphorylation of Ser621 and decreased activity of Raf-1. These results suggest that phosphorylation of Ser621 inactivates Raf-1, but do not prove that PKA is responsible for this in vivo.

SIGNOR-47148

Q9UBK2

P49760

0

phosphorylation

down-regulates activity

0.2

Clk2 could also repress PGC-1alpha activation of Foxo1 on the IRS response element , as well as repress the Pepck promoter .|Clk2 phosphorylates and represses PGC-1\u03b1.

SIGNOR-278228

Q92585

O60563

1

relocalization

up-regulates

0.2

Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.

SIGNOR-130712

P06241

P35613-2

1

phosphorylation

up-regulates activity

0.269

Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment.

SIGNOR-273999

O43164

P17612

0

phosphorylation

up-regulates activity

0.2

In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h).

SIGNOR-276316

Q71F56

Q969H0

0

ubiquitination

down-regulates quantity by destabilization

0.359

The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.

SIGNOR-266688

Q00535

O15516

1

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

P45983

Q96EB6

1

phosphorylation

up-regulates

0.601

Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53.

SIGNOR-162314

P05771

Q13131

1

phosphorylation

down-regulates activity

0.2

Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle.

SIGNOR-276460

P24941

P20248

1

phosphorylation

up-regulates

0.977

Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154

SIGNOR-74466

P36897

O75604

0

deubiquitination

up-regulates activity

0.2

Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1.

SIGNOR-273605

Q9NYV6

P45984

0

phosphorylation

down-regulates

0.472

Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation.

SIGNOR-134878

Q96PU5

P17612

0

phosphorylation

down-regulates

0.2

Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246).

SIGNOR-128429

Q14012

P49757

1

phosphorylation

down-regulates

0.334

Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2.

SIGNOR-149993

Q13535

Q02952

1

phosphorylation

up-regulates activity

0.2

The expression of either ATR-KD or the addition of the ATR kinase inhibitor VE-821 to ATR-WT expressing cells caused AKAP12 to be retained within the cytoplasm.|With UV damage, ATR phosphorylates AKAP12 at S732 which stimulates nuclear translocation of an AKAP12\u2013ATR-pS435 complex that results in enhanced 5\u2032 strand incision of NER.

SIGNOR-278292

Q15052

Q04759

0

phosphorylation

up-regulates activity

0.2

Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation.|More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway.

SIGNOR-272168

Q13905

P08631

0

phosphorylation

up-regulates

0.498

We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4.

SIGNOR-203613

Q96R06

Q9UNH5

0

dephosphorylation

down-regulates activity

0.2

We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment.

SIGNOR-277066

P49336

P36956

1

phosphorylation

up-regulates activity

0.474

Biochemical analyses reveal that SREBP-1c can be directly phosphorylated by CDK8 at the conserved Threonine-402 residue (T402) in vitro and in cultured mammalian cells ( xref ).|Therefore, the mechanism of CDK8 regulating SREBP functions is primarily through the phosphorylation initiated control of nuclear SREBP-1 protein stability.

SIGNOR-279688

P49768

Q05513

0

phosphorylation

up-regulates activity

0.337

A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.

SIGNOR-249239

P31749

P98170

1

phosphorylation

up-regulates quantity by stabilization

0.618

Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.

SIGNOR-119488

Q13114

Q96PU5

0

ubiquitination

up-regulates activity

0.27

Nedd4l promotes TRAF3 to interact with cIAP1/2 and HECTD3.|Ubiquitination of TRAF3 by Nedd4l promotes interaction of TRAF3 with proteins such as cIAP1/2, HECTD3, and TBK1.

SIGNOR-278587

O43474

Q7Z6Z7

0

ubiquitination

down-regulates quantity by destabilization

0.34

K48 linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression.|Instead, we identified the transcription factor KLF4 as a novel Mule substrate that is ubiquitinated by this E3 ligase and thus undergoes proteasomal degradation in T cells.|Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase.

SIGNOR-278749

P04150

P28482

0

phosphorylation

down-regulates activity

0.623

Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.

SIGNOR-249428

Q9UBS5

Q13554

0

phosphorylation

down-regulates quantity by destabilization

0.2

ERK1/2 and CaMKIIβ mediated phosphorylation of GABAB1 at serine 867 (S867) and threonine 872 (T872). We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1.

SIGNOR-277851

Q92630

O75449

1

phosphorylation

down-regulates quantity by destabilization

0.509

DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d).

SIGNOR-262847

P35222

O75582

0

phosphorylation

up-regulates activity

0.2

Co-transfection of MSK1 increased beta-catenin transcriptional activity in a dose dependent manner (XREF_FIG).|Our in vitro kinase assay showed that MSK1 can directly phosphorylate beta-catenin at Ser 552.

SIGNOR-278247

P08922

P18031

0

dephosphorylation

down-regulates

0.374

In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products.

SIGNOR-154199

P27361

Q96Q27

1

phosphorylation

up-regulates activity

0.265

Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation.

SIGNOR-272241

Q9HA82

P68400

0

phosphorylation

up-regulates activity

0.2

Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.

SIGNOR-273984

Q13153

O95863

1

phosphorylation

up-regulates

0.4

Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions.

SIGNOR-135605

P13569

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.471

Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination.

SIGNOR-272584

O95644

P17612

0

phosphorylation

down-regulates

0.385

Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)

SIGNOR-93531

Q13485

P28482

0

phosphorylation

up-regulates

0.511

Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276.

SIGNOR-101660

P04040

P00519

0

phosphorylation

up-regulates activity

0.403

C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases

SIGNOR-101302

Q96KB5

P12931

0

phosphorylation

up-regulates quantity by stabilization

0.395

Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon

SIGNOR-277217

Q9UNH5

P04637

1

dephosphorylation

down-regulates activity

0.401

The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification

SIGNOR-248828

O95271

P54274

1

ADP-ribosylation

down-regulates activity

0.803

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

SIGNOR-263377

P40763

P16591

0

phosphorylation

up-regulates activity

0.402

Replacing the unique 43-amino acid-long N-terminal tail of p51 (ferT) with a parallel segment from the N-terminal tail of p94 (fer) did not change the subcellular localization of p51 (ferT) but enabled it to activate Stat3.|When combined with immunoprecipitation analysis, this assay showed that p94 (fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2.

SIGNOR-279713

P51449

O00327

1

transcriptional regulation

up-regulates quantity by expression

0.502

As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression.

SIGNOR-268004

P06239

Q99704

1

phosphorylation

up-regulates activity

0.6

Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates.

SIGNOR-251373

Q16665

Q92544

1

transcriptional regulation

down-regulates quantity by repression

0.2

Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion.

SIGNOR-266705

P06493

O14994

1

phosphorylation

up-regulates

0.2

A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action.

SIGNOR-121398

P25098

Q96A54

1

phosphorylation

down-regulates activity

0.2

AdipoR1 is Directly Phosphorylated by GRK2.|In summary, our study demonstrates for the first time that cardiometabolic-regulatory, anti-inflammatory, and cardioprotective functions of APN are significantly impaired by GRK2 mediated AdipoR1 phosphorylative desensitization during a critical period of post-MI HF development.

SIGNOR-279463

Q00536

P46459

1

phosphorylation

down-regulates activity

0.439

Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self association of NSF.|We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569.

SIGNOR-279511

Q969K3

Q9UBK2

1

ubiquitination

down-regulates quantity by destabilization

0.319

Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.

SIGNOR-277912

O14640

Q9Y283

0

ubiquitination

down-regulates

0.641

Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation

SIGNOR-135766

Q8WYH8

P24941

0

phosphorylation

up-regulates quantity

0.401

We report that ING5 is phosphorylated in a cell cycle dependent manner by CDK2 at T152 (Figs 1 and 3).

SIGNOR-279447

P31751

P98170

1

phosphorylation

up-regulates

0.42

Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt.

SIGNOR-119492

Q9UNE7

Q8IXT1

1

ubiquitination

down-regulates quantity by destabilization

0.322

HSP70 recruits DDIAS to the CHIP E3 ligase, whereas CHIP promotes the ubiquitination of DDIAS.|However, the findings clearly demonstrated that HSP70 was solely involved in CHIP mediated proteasomal degradation of DDIAS.

SIGNOR-278784

P62714

P11233

1

dephosphorylation

down-regulates

0.289

Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function

SIGNOR-155349

P07948

O60711

1

phosphorylation

up-regulates activity

0.375

Of a total of 11 tyrosine sites in LPXN, we mutated Tyr(22), Tyr(72), Tyr(198), and Tyr(257) to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr(72) and that this tyrosine site is proximal to the LD3 domain. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr(72) is critical for the biological function of LPXN.

SIGNOR-262892

O14950

Q13153

0

phosphorylation

up-regulates activity

0.484

It has been shown that PAK1 phosphorylates and activates MLC2, leading to cell motility [ xref ].

SIGNOR-280053

P52732

Q9HC98

0

phosphorylation

up-regulates activity

0.444

Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.

SIGNOR-273886

P17252

Q8NF50

1

phosphorylation

down-regulates activity

0.2

In response to chemokine stimulation, PKC\u03b1 phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration.|Taken our data together, we suggest that PKC\u03b1 phosphorylates DOCK8 at the Ser2077/2082/2087 sites to promote T cell migration.

SIGNOR-279384

Q9Y2U5

P49023

1

phosphorylation

down-regulates quantity

0.362

As MEKK2 kinase activity is required for this function, our findings support a model of paxillin modification wherein MEKK2 directly phosphorylates and targets paxillin for ubiquitylation.

SIGNOR-278955

P14598

P27361

0

phosphorylation

up-regulates

0.42

Upon activation, several serine residues on the cytosolic oxidase subunit p47phox become phosphorylated. Mitogen-activated protein kinase phophorylated only the peptide containing ser345/348.

SIGNOR-40821

Q8TCJ2

Q9NZQ7

1

glycosylation

up-regulates quantity by stabilization

0.2

Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization.

SIGNOR-274976

O75385

Q9Y4P1

1

phosphorylation

down-regulates activity

0.614

Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316.|Thus ULK1 is able to inhibit LC3 processing by a direct effect on ATG4B, possibly by phosphorylation of a serine residue of ATG4B.Fig. 1ULK1 inhibits ATG4B-mediated LC3 cleavage. a Average ATG4B activity in Actin-LC3-DelN Luciferase HEK293T obtained by measuring the secreted luciferase activity 48 h after transfection with the indicated constructs (n = 3, average \u00b1 s.d.) and representative immunoblot from one experiment showing expression of the different constructs. b GST-LC3 assay to measure in vitro activity of recombinant ATG4B after incubation with active recombinant ULK1.

SIGNOR-279434

P49841

O43602

1

phosphorylation

up-regulates activity

0.271

Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact.

SIGNOR-170755

O15198

Q13485

1

phosphorylation

up-regulates

0.685

Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.

SIGNOR-168740

P06213

Q12923

0

dephosphorylation

down-regulates

0.26

We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.

SIGNOR-132555

P31751

Q6ZVD8

0

dephosphorylation

down-regulates activity

0.604

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-248729

Q06187

P19174

1

phosphorylation

up-regulates activity

0.581

Then, BTK and ITK are activated by Src kinases and proceed to phosphorylate the lipase PLCgamma2 / PLCgamma1, which cleaves PIP2 in the plasma membrane and generates the secondary messengers IP3 and DAG.

SIGNOR-279444

O00712

A8MYZ6

1

transcriptional regulation

down-regulates quantity

0.2

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

SIGNOR-268881

Q14164

Q04206

1

phosphorylation

up-regulates

0.439

Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.

SIGNOR-129943

P01019-PRO_0000032458

P12821

0

cleavage

up-regulates quantity

0.2

Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I

SIGNOR-260236

P15172

P17661

1

transcriptional regulation

down-regulates quantity by repression

0.24

MyoD and HDAC2 repress myogenic late genes at early times of differentiation.A time course of Ckm, Des and Acta1 gene expression demonstrated that these genes were prematurely expressed when differentiation was driven by myogenin and Mef2D1b (Figure _(Figure6A).6A). Since MyoD is not expressed under these conditions, it cannot bind to these genes; ChIP assays demonstrated that HDAC2 also was not present on the Ckm, Des and Acta1 regulatory sequences under these conditions (Figure _(Figure6B).6B). Therefore the presence of MyoD and HDAC2 prior to gene expression functions to repress late gene expression at early times of differentiation.

SIGNOR-241762

Q15154

P51955

1

relocalization

up-regulates

0.425

Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1

SIGNOR-133337

P06493

Q8TD19

1

phosphorylation

up-regulates activity

0.482

We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1.

SIGNOR-273889

P23634-6

Q05397

0

phosphorylation

up-regulates activity

0.2

Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif.

SIGNOR-263194

Q16584

Q92918

0

phosphorylation

up-regulates

0.574

Hpk1 also phosphorylated mlk-3 activation loop in vitro, and ser281 was found to be the major phosphorylation site, indicating that hpk1 also activates mlk-3 via phosphorylation of the kinase activation loop.

SIGNOR-83415

O75925

Q5U5R9

0

polyubiquitination

down-regulates quantity by destabilization

0.389

We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model.

SIGNOR-272421

Q14493

Q16695

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-265417

P54132

Q86YT6

0

ubiquitination

down-regulates quantity by destabilization

0.281

BLM is Ubiquitinated by E3 Ligase MIB1.|Moreover, MIB1 mediated BLM degradation in G1 phase appears to be important for DNA double-strand break repair.

SIGNOR-278548

Q07812

Q9UPU5

0

deubiquitination

up-regulates quantity by stabilization

0.2

In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels

SIGNOR-275606

Q5JVS0

Q05655

0

phosphorylation

down-regulates activity

0.29

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249254

Q12778

Q9HCE7

1

transcriptional regulation

up-regulates quantity

0.248

FoxO factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1), leading to the ubiquitylation of myosin and other muscle proteins (see below), and their degradation via the proteasome

SIGNOR-256268

O15294

Q01813

1

glycosylation

down-regulates activity

0.257

Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.

SIGNOR-267583

O75581

P28482

0

phosphorylation

up-regulates

0.301

We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.

SIGNOR-169001

Q9UN37

Q9Y3E7

1

cleavage

up-regulates activity

0.625

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

SIGNOR-260847

P19784

Q92769

1

phosphorylation

up-regulates activity

0.39

HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2.

SIGNOR-251001

Q8NB16

Q9Y572

0

phosphorylation

up-regulates activity

0.753

MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays

SIGNOR-266427

P11831

P17612

0

phosphorylation

up-regulates

0.256

Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.

SIGNOR-188177

P06730

Q9UDX5

1

translation regulation

up-regulates activity

0.2

In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1

SIGNOR-275429

Q9GZV5

P06493

0

phosphorylation

down-regulates activity

0.258

We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity

SIGNOR-276518

Q9H3D4

P24941

0

phosphorylation

down-regulates

0.246

Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively

SIGNOR-180759

Q9UHD2

Q04206

1

phosphorylation

up-regulates

0.614

Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.

SIGNOR-129951

P05412

P00519

0

phosphorylation

up-regulates activity

0.526

Active nuclear Abl efficiently phosphorylate c-Jun. After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl.

SIGNOR-251428

P49023

Q99942

0

ubiquitination

down-regulates quantity

0.407

Here we demonstrate that the human homologue of RNF5 associates with the amino-terminal domain of paxillin, resulting in its ubiquitination. RNF5 requires intact RING and C-terminal domains to mediate paxillin ubiquitination. Concomitantly, RNF5 expression results in inhibition of cell motility. Via targeting of paxillin ubiquitination, which alters its localization, RNF5 emerges as a novel regulator of cell motility.

SIGNOR-271479

P28482

P04150

1

phosphorylation

down-regulates activity

0.623

Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.

SIGNOR-249428

P42858

Q00535

0

phosphorylation

up-regulates

0.447

Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.

SIGNOR-156840

P00533

P48050

1

phosphorylation

up-regulates activity

0.2

These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K(IR) 2.3 channel via phosphorylation of the Y234 residue of the WT protein.

SIGNOR-276322

Q9BZS1

P84022

0

null

up-regulates

0.523

The TCR, IL-2R, and TbetaR must all be stimulated to induce Foxp3 + Tregs. Failure to engage any one of these receptors prevents the generation of Foxp3 + Tregs

SIGNOR-254363

P05412

P04150

0

transcriptional regulation

down-regulates quantity by repression

0.743

We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins

SIGNOR-251679

Q8WU20

P22455

0

phosphorylation

up-regulates activity

0.685

In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.

SIGNOR-242661

P13640

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.286

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. The expression of MT1G during ferroptosis is regulated by the NFE2L2 signaling pathway. In the context of cancer, particularly HCC, the upregulation of MT1G has been linked to resistance against sorafenib, a kinase inhibitor commonly used in cancer therapy

SIGNOR-279866

O43781

Q9Y6Q9

1

phosphorylation

down-regulates activity

0.2

Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity.

SIGNOR-275451

P50616

P27361

0

phosphorylation

down-regulates

0.352

Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk

SIGNOR-88728

Q9Y463

P20823

1

phosphorylation

up-regulates

0.502

Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk

SIGNOR-86728