GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q7KZI7	Q92974	1	phosphorylation	down-regulates	0.503	We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation	SIGNOR-177100
Q14974	P84022	1	relocalization	up-regulates	0.524	Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation.	SIGNOR-78191
P29372	Q13315	0	phosphorylation	up-regulates activity	0.265	ATM phosphorylates MPG at serine 172 (XREF_FIG).\|In summary, our results show that ATM and MPG are directly associated in vitro and in vivo, phosphorylation of MPG at serine 172 is dependent on ATM and that of loss of phospho ATM reduces MPG glycosylase activity.	SIGNOR-279004
Q16539	P11362	1	phosphorylation	down-regulates	0.274	Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777	SIGNOR-166598
P49336	P84022	1	phosphorylation	down-regulates	0.566	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161557
Q13131	O15503	1	phosphorylation	up-regulates quantity by stabilization	0.256	Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner.	SIGNOR-277430
P07384	P55085	1	cleavage	down-regulates activity	0.298	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263580
P35716	Q9HCK8	0	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268923
P34947	Q16143	1	phosphorylation	down-regulates activity	0.321	GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5	SIGNOR-251203
Q92835	P43405	1	dephosphorylation	down-regulates activity	0.418	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268456
O14965	Q13526	1	phosphorylation	down-regulates activity	0.254	Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry.	SIGNOR-202487
Q05513	Q96A00	1	phosphorylation	up-regulates activity	0.277	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249261
P09493	P42336	0	phosphorylation	up-regulates activity	0.2	Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization.	SIGNOR-263027
Q14134	P49137	0	phosphorylation	up-regulates activity	0.307	ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC.	SIGNOR-273675
Q14012	Q9Y570	1	phosphorylation	up-regulates activity	0.395	CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15	SIGNOR-277827
Q15118	P08559	1	phosphorylation	down-regulates activity	0.794	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109551
P24864	P49841	0	phosphorylation	down-regulates	0.445	Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380	SIGNOR-118563
P98170	P31751	0	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
Q16539	Q15256	0	dephosphorylation	down-regulates	0.558	As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl.	SIGNOR-111762
O75030	P63279	0	ubiquitination	down-regulates	0.565	Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo.	SIGNOR-75117
P06493	Q8IWB6	1	phosphorylation	down-regulates quantity by destabilization	0.333	Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction	SIGNOR-273524
Q9P0L2	Q15831	0	phosphorylation	up-regulates	0.41	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122545
P62136	P27708	1	dephosphorylation	down-regulates activity	0.332	Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2\| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys \| Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2.	SIGNOR-263741
P12931	P10301	1	phosphorylation	down-regulates activity	0.58	The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66	SIGNOR-111189
P14784	P29350	0	dephosphorylation	down-regulates	0.532	We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3.	SIGNOR-55989
Q96T88	Q5T3J3	1	ubiquitination	down-regulates activity	0.2	In our study, we found the UHRF1 is sufficient to suppress RIF1 accumulation at DSBs in S phase and CtIP functions as a negative regulator of RIF1 only in G2 phase (XREF_FIG; XREF_SUPPLEMENTARY).\|UHRF1 ubiquitinates RIF1.	SIGNOR-278604
P29353	P17252	0	phosphorylation	up-regulates activity	0.401	Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.	SIGNOR-249150
Q9UBF8	Q9BZL6	0	phosphorylation	up-regulates	0.2	Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity.	SIGNOR-148880
P30307	P53350	0	phosphorylation	up-regulates	0.804	The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase.	SIGNOR-115993
P07949	P42224	1	phosphorylation	up-regulates activity	0.275	In detail, RET and PTC3 induced STAT1 overexpression and phosphorylation at Ser 727 and Tyr 701.	SIGNOR-279276
P11309	O60381	1	phosphorylation	up-regulates activity	0.2	Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it.	SIGNOR-277346
Q13158	P48729	0	phosphorylation	down-regulates activity	0.333	FADD is essential for death receptor (DR)-induced apoptosis.\|Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities	SIGNOR-139307
Q07820	P49840	0	phosphorylation	down-regulates quantity by destabilization	0.457	MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein	SIGNOR-251217
P17676	Q8N695	1	transcriptional regulation	up-regulates quantity by expression	0.2	Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.	SIGNOR-254054
P55211	P06493	0	phosphorylation	down-regulates	0.429	Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.	SIGNOR-141621
Q53GL7	P53350	0	phosphorylation	up-regulates activity	0.2	PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development.	SIGNOR-273728
P09917	Q9UQM7	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export\|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques\|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO.	SIGNOR-264408
O75925	Q13485	1	sumoylation	up-regulates	0.394	These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4	SIGNOR-123462
P24666	P09619	1	dephosphorylation	down-regulates activity	0.308	Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation\|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors.	SIGNOR-248452
O95292	Q14721	0	relocalization	up-regulates quantity	0.2	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.\|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262121
Q6P1N0	P06493	0	phosphorylation	up-regulates activity	0.2	We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation.	SIGNOR-268297
P16410	O60674	0	phosphorylation	up-regulates quantity by stabilization	0.445	Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules.	SIGNOR-251346
P51812	P16220	1	phosphorylation	up-regulates activity	0.726	MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression	SIGNOR-248951
P06748	P06493	0	phosphorylation	down-regulates activity	0.518	However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.	SIGNOR-89605
P21796	Q96PY6	0	phosphorylation	down-regulates	0.424	Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux.	SIGNOR-164222
P12931	Q9Y4K3	1	phosphorylation	up-regulates activity	0.565	To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation.	SIGNOR-277866
P06493	O75306	1	phosphorylation	up-regulates activity	0.2	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.\|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation	SIGNOR-275592
P48729	P35222	1	phosphorylation	down-regulates	0.791	Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome	SIGNOR-165022
P27986	P22681	0	ubiquitination	down-regulates	0.694	Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.	SIGNOR-110060
Q9UBF6	P21359	1	ubiquitination	down-regulates activity	0.249	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.	SIGNOR-271453
Q8IXL6	Q96HE7	1	phosphorylation	up-regulates activity	0.2	We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding.	SIGNOR-277395
P08575	P29597	1	dephosphorylation	down-regulates activity	0.407	CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling\|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells	SIGNOR-248357
Q13586	P06493	0	phosphorylation	down-regulates	0.345	Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce.	SIGNOR-189017
Q14106	P11802	0	phosphorylation	up-regulates activity	0.2	Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation.	SIGNOR-273602
Q02447	P27361	0	phosphorylation	up-regulates	0.299	Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73.	SIGNOR-157276
Q9NYL2	Q16512	0	phosphorylation	up-regulates	0.2	Phosphorylation of mltkalpha by pknalpha enhances its kinase activity	SIGNOR-152768
Q13144	P49841	0	phosphorylation	down-regulates activity	0.579	The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535).	SIGNOR-251236
P27361	P07949	0	phosphorylation	up-regulates	0.433	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140298
O60716	P12931	0	phosphorylation	up-regulates activity	0.922	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246484
Q08209	Q13469	1	dephosphorylation	up-regulates activity	0.629	NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248690
P98082	Q05655	0	phosphorylation	down-regulates	0.296	Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.	SIGNOR-127198
O96017	Q01094	1	phosphorylation	up-regulates quantity by stabilization	0.487	We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage	SIGNOR-100898
Q92831	Q71DI3	1	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269626
Q01196	P06493	0	phosphorylation	up-regulates	0.341	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-169322
Q13247	Q13627	0	phosphorylation	up-regulates activity	0.432	These results suggest that Dyrk1A enhances SRp55 promoted cTnT exon 5 inclusion.\|These results supported the finding that phosphorylation of SRp55 by Dyrk1A promotes cTnT exon 5 inclusion.Alternative splicing of cTnT exon 5 is regulated developmentally.	SIGNOR-279166
P06493	P62820	1	phosphorylation	down-regulates activity	0.526	We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells.	SIGNOR-261284
Q99967	P28482	0	phosphorylation	up-regulates activity	0.454	CITED2 coactivation is enhanced by activation of MAPK1 and requires T166.\|CITED2 is phosphorylated by MAPK1 at S85, T166 and T175.	SIGNOR-278410
P19174	P12931	0	phosphorylation	up-regulates activity	0.636	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-247316
P49116	P22888	1	transcriptional regulation	up-regulates quantity by expression	0.2	Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.	SIGNOR-266217
P04150	Q00535	0	phosphorylation	down-regulates activity	0.481	Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.\| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue	SIGNOR-154405
O43293	P04637	1	phosphorylation	up-regulates	0.406	A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53.	SIGNOR-153495
P83916	P68400	0	phosphorylation	down-regulates	0.303	Two recent papers suggest that hp1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Our findings reconcile recent findings in a new model, wherein rapid hp1beta mobilization from dsbs is mediated by its phosphorylation on thr51 by ck2	SIGNOR-187450
P07101	P49137	0	phosphorylation	up-regulates activity	0.52	MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation.	SIGNOR-250149
Q6PHR2	P10070	1	phosphorylation	up-regulates activity	0.621	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro	SIGNOR-260798
Q07960	P61586	1	gtpase-activating protein	down-regulates activity	0.864	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260458
P46734	P53778	1	phosphorylation	up-regulates	0.648	Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro.	SIGNOR-83718
Q12857	P15172	1	transcriptional regulation	up-regulates quantity by expression	0.246	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263982
P12821	P01019	1	cleavage	up-regulates activity	0.782	Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide.	SIGNOR-253326
P56817	Q00535	0	phosphorylation	up-regulates activity	0.44	BACE1 is phosphorylated by p25 and Cdk5 at Thr252.\|Our finding that p25/Cdk5 stimulates BACE1 activity supports that p25/Cdk5 may represent a promising target for the development of drugs to treat Alzheimer's disease.	SIGNOR-278249
O75581	P17612	0	phosphorylation	up-regulates activity	0.2	These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit.	SIGNOR-181979
Q92934	Q15349	0	phosphorylation	down-regulates	0.373	The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.	SIGNOR-184591
P31751	Q9GZV1	1	phosphorylation	up-regulates	0.414	In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions.	SIGNOR-236978
P28482	Q9NZV8	1	phosphorylation	up-regulates activity	0.367	We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP.	SIGNOR-262935
P04150	Q9UNS1	1	transcriptional regulation	up-regulates quantity by expression	0.252	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268052
P07954	O96013	0	phosphorylation	down-regulates quantity	0.2	FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation.	SIGNOR-266315
Q02363	P24941	0	phosphorylation	down-regulates	0.434	Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_	SIGNOR-46397
Q8NHW3	P49840	0	phosphorylation	up-regulates activity	0.2	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /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./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159377
P01106	P00519	0	phosphorylation	up-regulates activity	0.469	Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.\|These experiments confirmed that Myc Y74 is phosphorylated by Abl, and provided us with a reagent to detect this form of Myc in cells (see below).	SIGNOR-278196
Q9H0A0	Q00987	1	ubiquitination	down-regulates quantity by destabilization	0.33	NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.	SIGNOR-272405
Q00987	P04637	1	ubiquitination	down-regulates quantity by destabilization	0.968	The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2.	SIGNOR-196116
P12931	Q15306	1	phosphorylation	up-regulates activity	0.273	Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation.\|We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target B cell integration cluster in Epstein-Barr virus-transformed cells.	SIGNOR-279287
Q9Y5P4	Q5SGD2	0	dephosphorylation	up-regulates activity	0.2	The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.\|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.	SIGNOR-277113
P06737	P15735	0	phosphorylation	up-regulates activity	0.656	It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267401
Q13976	Q13507-3	1	phosphorylation	down-regulates	0.408	The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263.	SIGNOR-142957
Q96EA4	Q70EL2	0	deubiquitination	up-regulates activity	0.2	Spindly is mono-ubiquitylated and this ubiquitin can be removed by active USP45. K48 ubiquitylated complex that interacts with Spindly is also de-ubiquitylated by USP45. In the absence of USP45 catalytic activity, interaction is abolished and cell migration is affected similarly to the phenotype described for lack of Spindly.	SIGNOR-268505
P49137	O75925	1	phosphorylation	up-regulates	0.2	T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity.	SIGNOR-199944
P28482	P84022	1	phosphorylation	down-regulates activity	0.746	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161613
P13639	P41240	0	phosphorylation	down-regulates quantity	0.264	C-terminal Src kinase (Csk)-mediated phosphorylation of eukaryotic elongation factor 2 (eEF2) promotes proteolytic cleavage and nuclear translocation of eEF2.\|In this report, we show that eukaryotic elongation factor 2 (eEF2) is a new protein substrate of Csk and could locate in the nucleus.	SIGNOR-279698
Q9NQ66	O14641	0	null	up-regulates activity	0.268	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258979
Q13315	Q8NHY2	1	phosphorylation	down-regulates	0.2	Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism	SIGNOR-149082

Q7KZI7

Q92974

1

phosphorylation

down-regulates

0.503

We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation

SIGNOR-177100

Q14974

P84022

1

relocalization

up-regulates

0.524

Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation.

SIGNOR-78191

P29372

Q13315

0

phosphorylation

up-regulates activity

0.265

ATM phosphorylates MPG at serine 172 (XREF_FIG).|In summary, our results show that ATM and MPG are directly associated in vitro and in vivo, phosphorylation of MPG at serine 172 is dependent on ATM and that of loss of phospho ATM reduces MPG glycosylase activity.

SIGNOR-279004

Q16539

P11362

1

phosphorylation

down-regulates

0.274

Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777

SIGNOR-166598

P49336

P84022

1

phosphorylation

down-regulates

0.566

Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.

SIGNOR-161557

Q13131

O15503

1

phosphorylation

up-regulates quantity by stabilization

0.256

Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner.

SIGNOR-277430

P07384

P55085

1

cleavage

down-regulates activity

0.298

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3

SIGNOR-263580

P35716

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.2

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

SIGNOR-268923

P34947

Q16143

1

phosphorylation

down-regulates activity

0.321

GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5

SIGNOR-251203

Q92835

P43405

1

dephosphorylation

down-regulates activity

0.418

An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.

SIGNOR-268456

O14965

Q13526

1

phosphorylation

down-regulates activity

0.254

Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry.

SIGNOR-202487

Q05513

Q96A00

1

phosphorylation

up-regulates activity

0.277

A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.

SIGNOR-249261

P09493

P42336

0

phosphorylation

up-regulates activity

0.2

Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization.

SIGNOR-263027

Q14134

P49137

0

phosphorylation

up-regulates activity

0.307

ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC.

SIGNOR-273675

Q14012

Q9Y570

1

phosphorylation

up-regulates activity

0.395

CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15

SIGNOR-277827

Q15118

P08559

1

phosphorylation

down-regulates activity

0.794

Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.

SIGNOR-109551

P24864

P49841

0

phosphorylation

down-regulates

0.445

Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380

SIGNOR-118563

P98170

P31751

0

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

Q16539

Q15256

0

dephosphorylation

down-regulates

0.558

As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl.

SIGNOR-111762

O75030

P63279

0

ubiquitination

down-regulates

0.565

Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo.

SIGNOR-75117

P06493

Q8IWB6

1

phosphorylation

down-regulates quantity by destabilization

0.333

Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction

SIGNOR-273524

Q9P0L2

Q15831

0

phosphorylation

up-regulates

0.41

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122545

P62136

P27708

1

dephosphorylation

down-regulates activity

0.332

Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2.

SIGNOR-263741

P12931

P10301

1

phosphorylation

down-regulates activity

0.58

The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66

SIGNOR-111189

P14784

P29350

0

dephosphorylation

down-regulates

0.532

We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3.

SIGNOR-55989

Q96T88

Q5T3J3

1

ubiquitination

down-regulates activity

0.2

In our study, we found the UHRF1 is sufficient to suppress RIF1 accumulation at DSBs in S phase and CtIP functions as a negative regulator of RIF1 only in G2 phase (XREF_FIG; XREF_SUPPLEMENTARY).|UHRF1 ubiquitinates RIF1.

SIGNOR-278604

P29353

P17252

0

phosphorylation

up-regulates activity

0.401

Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.

SIGNOR-249150

Q9UBF8

Q9BZL6

0

phosphorylation

up-regulates

0.2

Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity.

SIGNOR-148880

P30307

P53350

0

phosphorylation

up-regulates

0.804

The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase.

SIGNOR-115993

P07949

P42224

1

phosphorylation

up-regulates activity

0.275

In detail, RET and PTC3 induced STAT1 overexpression and phosphorylation at Ser 727 and Tyr 701.

SIGNOR-279276

P11309

O60381

1

phosphorylation

up-regulates activity

0.2

Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it.

SIGNOR-277346

Q13158

P48729

0

phosphorylation

down-regulates activity

0.333

FADD is essential for death receptor (DR)-induced apoptosis.|Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities

SIGNOR-139307

Q07820

P49840

0

phosphorylation

down-regulates quantity by destabilization

0.457

MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein

SIGNOR-251217

P17676

Q8N695

1

transcriptional regulation

up-regulates quantity by expression

0.2

Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.

SIGNOR-254054

P55211

P06493

0

phosphorylation

down-regulates

0.429

Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.

SIGNOR-141621

Q53GL7

P53350

0

phosphorylation

up-regulates activity

0.2

PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development.

SIGNOR-273728

P09917

Q9UQM7

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO.

SIGNOR-264408

O75925

Q13485

1

sumoylation

up-regulates

0.394

These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4

SIGNOR-123462

P24666

P09619

1

dephosphorylation

down-regulates activity

0.308

Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors.

SIGNOR-248452

O95292

Q14721

0

relocalization

up-regulates quantity

0.2

Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.

SIGNOR-262121

Q6P1N0

P06493

0

phosphorylation

up-regulates activity

0.2

We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation.

SIGNOR-268297

P16410

O60674

0

phosphorylation

up-regulates quantity by stabilization

0.445

Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules.

SIGNOR-251346

P51812

P16220

1

phosphorylation

up-regulates activity

0.726

MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression

SIGNOR-248951

P06748

P06493

0

phosphorylation

down-regulates activity

0.518

However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.

SIGNOR-89605

P21796

Q96PY6

0

phosphorylation

down-regulates

0.424

Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux.

SIGNOR-164222

P12931

Q9Y4K3

1

phosphorylation

up-regulates activity

0.565

To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation.

SIGNOR-277866

P06493

O75306

1

phosphorylation

up-regulates activity

0.2

Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation

SIGNOR-275592

P48729

P35222

1

phosphorylation

down-regulates

0.791

Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome

SIGNOR-165022

P27986

P22681

0

ubiquitination

down-regulates

0.694

Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.

SIGNOR-110060

Q9UBF6

P21359

1

ubiquitination

down-regulates activity

0.249

SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.

SIGNOR-271453

Q8IXL6

Q96HE7

1

phosphorylation

up-regulates activity

0.2

We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding.

SIGNOR-277395

P08575

P29597

1

dephosphorylation

down-regulates activity

0.407

CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells

SIGNOR-248357

Q13586

P06493

0

phosphorylation

down-regulates

0.345

Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce.

SIGNOR-189017

Q14106

P11802

0

phosphorylation

up-regulates activity

0.2

Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation.

SIGNOR-273602

Q02447

P27361

0

phosphorylation

up-regulates

0.299

Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73.

SIGNOR-157276

Q9NYL2

Q16512

0

phosphorylation

up-regulates

0.2

Phosphorylation of mltkalpha by pknalpha enhances its kinase activity

SIGNOR-152768

Q13144

P49841

0

phosphorylation

down-regulates activity

0.579

The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535).

SIGNOR-251236

P27361

P07949

0

phosphorylation

up-regulates

0.433

We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).

SIGNOR-140298

O60716

P12931

0

phosphorylation

up-regulates activity

0.922

Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302

SIGNOR-246484

Q08209

Q13469

1

dephosphorylation

up-regulates activity

0.629

NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity

SIGNOR-248690

P98082

Q05655

0

phosphorylation

down-regulates

0.296

Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.

SIGNOR-127198

O96017

Q01094

1

phosphorylation

up-regulates quantity by stabilization

0.487

We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage

SIGNOR-100898

Q92831

Q71DI3

1

acetylation

down-regulates activity

0.2

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

SIGNOR-269626

Q01196

P06493

0

phosphorylation

up-regulates

0.341

Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).

SIGNOR-169322

Q13247

Q13627

0

phosphorylation

up-regulates activity

0.432

These results suggest that Dyrk1A enhances SRp55 promoted cTnT exon 5 inclusion.|These results supported the finding that phosphorylation of SRp55 by Dyrk1A promotes cTnT exon 5 inclusion.Alternative splicing of cTnT exon 5 is regulated developmentally.

SIGNOR-279166

P06493

P62820

1

phosphorylation

down-regulates activity

0.526

We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells.

SIGNOR-261284

Q99967

P28482

0

phosphorylation

up-regulates activity

0.454

CITED2 coactivation is enhanced by activation of MAPK1 and requires T166.|CITED2 is phosphorylated by MAPK1 at S85, T166 and T175.

SIGNOR-278410

P19174

P12931

0

phosphorylation

up-regulates activity

0.636

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

SIGNOR-247316

P49116

P22888

1

transcriptional regulation

up-regulates quantity by expression

0.2

Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.

SIGNOR-266217

P04150

Q00535

0

phosphorylation

down-regulates activity

0.481

Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue

SIGNOR-154405

O43293

P04637

1

phosphorylation

up-regulates

0.406

A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53.

SIGNOR-153495

P83916

P68400

0

phosphorylation

down-regulates

0.303

Two recent papers suggest that hp1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Our findings reconcile recent findings in a new model, wherein rapid hp1beta mobilization from dsbs is mediated by its phosphorylation on thr51 by ck2

SIGNOR-187450

P07101

P49137

0

phosphorylation

up-regulates activity

0.52

MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation.

SIGNOR-250149

Q6PHR2

P10070

1

phosphorylation

up-regulates activity

0.621

We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro

SIGNOR-260798

Q07960

P61586

1

gtpase-activating protein

down-regulates activity

0.864

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260458

P46734

P53778

1

phosphorylation

up-regulates

0.648

Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro.

SIGNOR-83718

Q12857

P15172

1

transcriptional regulation

up-regulates quantity by expression

0.246

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263982

P12821

P01019

1

cleavage

up-regulates activity

0.782

Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide.

SIGNOR-253326

P56817

Q00535

0

phosphorylation

up-regulates activity

0.44

BACE1 is phosphorylated by p25 and Cdk5 at Thr252.|Our finding that p25/Cdk5 stimulates BACE1 activity supports that p25/Cdk5 may represent a promising target for the development of drugs to treat Alzheimer's disease.

SIGNOR-278249

O75581

P17612

0

phosphorylation

up-regulates activity

0.2

These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit.

SIGNOR-181979

Q92934

Q15349

0

phosphorylation

down-regulates

0.373

The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.

SIGNOR-184591

P31751

Q9GZV1

1

phosphorylation

up-regulates

0.414

In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions.

SIGNOR-236978

P28482

Q9NZV8

1

phosphorylation

up-regulates activity

0.367

We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP.

SIGNOR-262935

P04150

Q9UNS1

1

transcriptional regulation

up-regulates quantity by expression

0.252

GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription

SIGNOR-268052

P07954

O96013

0

phosphorylation

down-regulates quantity

0.2

FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation.

SIGNOR-266315

Q02363

P24941

0

phosphorylation

down-regulates

0.434

Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_

SIGNOR-46397

Q8NHW3

P49840

0

phosphorylation

up-regulates activity

0.2

We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /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./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.

SIGNOR-159377

P01106

P00519

0

phosphorylation

up-regulates activity

0.469

Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.|These experiments confirmed that Myc Y74 is phosphorylated by Abl, and provided us with a reagent to detect this form of Myc in cells (see below).

SIGNOR-278196

Q9H0A0

Q00987

1

ubiquitination

down-regulates quantity by destabilization

0.33

NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.

SIGNOR-272405

Q00987

P04637

1

ubiquitination

down-regulates quantity by destabilization

0.968

The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2.

SIGNOR-196116

P12931

Q15306

1

phosphorylation

up-regulates activity

0.273

Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation.|We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target B cell integration cluster in Epstein-Barr virus-transformed cells.

SIGNOR-279287

Q9Y5P4

Q5SGD2

0

dephosphorylation

up-regulates activity

0.2

The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.

SIGNOR-277113

P06737

P15735

0

phosphorylation

up-regulates activity

0.656

It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15

SIGNOR-267401

Q13976

Q13507-3

1

phosphorylation

down-regulates

0.408

The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263.

SIGNOR-142957

Q96EA4

Q70EL2

0

deubiquitination

up-regulates activity

0.2

Spindly is mono-ubiquitylated and this ubiquitin can be removed by active USP45. K48 ubiquitylated complex that interacts with Spindly is also de-ubiquitylated by USP45. In the absence of USP45 catalytic activity, interaction is abolished and cell migration is affected similarly to the phenotype described for lack of Spindly.

SIGNOR-268505

P49137

O75925

1

phosphorylation

up-regulates

0.2

T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity.

SIGNOR-199944

P28482

P84022

1

phosphorylation

down-regulates activity

0.746

Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3

SIGNOR-161613

P13639

P41240

0

phosphorylation

down-regulates quantity

0.264

C-terminal Src kinase (Csk)-mediated phosphorylation of eukaryotic elongation factor 2 (eEF2) promotes proteolytic cleavage and nuclear translocation of eEF2.|In this report, we show that eukaryotic elongation factor 2 (eEF2) is a new protein substrate of Csk and could locate in the nucleus.

SIGNOR-279698

Q9NQ66

O14641

0

null

up-regulates activity

0.268

Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin

SIGNOR-258979

Q13315

Q8NHY2

1

phosphorylation

down-regulates

0.2

Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism

SIGNOR-149082